RBCC Red Blood Cell Collection

HBB [Confidence: high (present in two of the MS resources)]
Hemoglobin subunit beta (Beta-globin; Hemoglobin beta chain; LVV-hemorphin-7; Spinorphin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P68871
ID HBB_HUMAN Reviewed; 147 AA.
AC P68871; A4GX73; B2ZUE0; P02023; Q13852; Q14481; Q14510; Q45KT0;
read moreAC Q549N7; Q6FI08; Q6R7N2; Q8IZI1; Q9BX96; Q9UCD6; Q9UCP8; Q9UCP9;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Hemoglobin subunit beta;
DE AltName: Full=Beta-globin;
DE AltName: Full=Hemoglobin beta chain;
DE Contains:
DE RecName: Full=LVV-hemorphin-7;
DE Contains:
DE RecName: Full=Spinorphin;
GN Name=HBB;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1019344;
RA Marotta C., Forget B., Cohen-Solal M., Weissman S.M.;
RT "Nucleotide sequence analysis of coding and noncoding regions of human
RT beta-globin mRNA.";
RL Prog. Nucleic Acid Res. Mol. Biol. 19:165-175(1976).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6254664; DOI=10.1016/0092-8674(80)90428-6;
RA Lawn R.M., Efstratiadis A., O'Connell C., Maniatis T.;
RT "The nucleotide sequence of the human beta-globin gene.";
RL Cell 21:647-651(1980).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-7.
RX PubMed=16175509; DOI=10.1086/491748;
RA Wood E.T., Stover D.A., Slatkin M., Nachman M.W., Hammer M.F.;
RT "The beta-globin recombinational hotspot reduces the effects of strong
RT selection around HbC, a recently arisen mutation providing resistance
RT to malaria.";
RL Am. J. Hum. Genet. 77:637-642(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Lu L., Hu Z.H., Du C.S., Fu Y.S.;
RT "DNA sequence of the human beta-globin gene isolated from a healthy
RT Chinese.";
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-113.
RA Cabeda J.M., Correia C., Estevinho A., Cardoso C., Amorim M.L.,
RA Cleto E., Vale L., Coimbra E., Pinho L., Justica B.;
RT "Unexpected patterns of globin mutations in thalassemia patients from
RT north of Portugal.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT LOUISVILLE LEU-43.
RC TISSUE=Blood;
RA Kutlar F., Harbin J., Brisco J., Kutlar A.;
RT "Rapid detection of electrophoretically silent, unstable human
RT hemoglobin 'Louisville', (Beta; Phe 42 Leu/TTT to CTT) by cDNA
RT sequencing of mRNA.";
RL Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT DURHAM-N.C. PRO-115.
RC TISSUE=Blood;
RA Kutlar F., Abboud M., Leithner C., Holley L., Brisco J., Kutlar A.;
RT "Electrophoretically silent, very unstable, thalassemic mutation at
RT codon 114 of beta globin (hemoglobin Durham-N.C.) detected by cDNA
RT sequencing of mRNA, from a Russian women.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT TY GARD GLN-125.
RC TISSUE=Blood;
RA Kutlar F., Holley L., Leithner C., Kutlar A.;
RT "A rare beta chain variant 'Hemoglobin Ty Gard:Pro 124 Gln' found in a
RT Caucasian female with erythrocytosis.";
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Kutlar A., Vercellotti G.M., Glendenning M., Holley L., Elam D.,
RA Kutlar F.;
RT "Heterozygote C->A beta-thalassemia mutation at the intron-2/848
RT nucleotide of beta globin gene was detected on a Northern European
RT (Caucasian) individual.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-7 AND SER-140.
RC TISSUE=Blood;
RA Kutlar F., Lallinger R.R., Holley L., Glendenning M., Kutlar A.;
RT "A new hemoglobin, beta chain variant 'Hb S-Wake' confirmed to be on
RT the same chromosome with hemoglobin S mutation, detected in an
RT African-American family.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT O-ARAB.
RC TISSUE=Blood;
RA Kutlar F., Elam D., Glendenning M., Kutlar A., Dincol G.;
RT "Coexistence of the hemoglobin O-Arab (Glu 121 Lys) and beta-
RT thalassemia (intron-2; nucleotide 745 C->G) was detected in a Turkish
RT patient.";
RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Li W.J.;
RT "Thalassaemic trait cause by C-T substitution at position -90 in
RT proximal CACCC box of beta-globin gene in China family.";
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS PHE-50 AND PRO-76.
RC TISSUE=Lymphocyte;
RA Fan B., Xie L., Guan X.;
RT "The differently expressed genes in the lymphocyte of recovered SARS
RT patients.";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RA Mehta S., Li T., Davis D.H., Nechtman J., Kutlar F.;
RT "Beta-thalassemia G->C mutation at the nucleotide 5 position of intron
RT 1 of beta globin gene was detected in Asian-Indian female with two
RT polymorphisms in cis.";
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Hilliard L.M., Patel N., Li T., Zhang H., Kutlar A., Kutlar F.;
RT "Hb Dothan: a novel beta chain variant due to (-GTG) deletion between
RT the codons 25/26 of beta globin gene detected in a Caucasian male
RT baby.";
RL Submitted (MAY-2008) to the EMBL/GenBank/DDBJ databases.
RN [16]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [17]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [18]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [19]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [20]
RP PROTEIN SEQUENCE OF 2-147.
RX PubMed=13872627;
RA Braunitzer G., Gehring-Muller R., Hilschmann N., Hilse K., Hobom G.,
RA Rudloff V., Wittmann-Liebold B.;
RT "The constitution of normal adult human haemoglobin.";
RL Hoppe-Seyler's Z. Physiol. Chem. 325:283-286(1961).
RN [21]
RP PROTEIN SEQUENCE OF 33-42, AND MASS SPECTROMETRY.
RX PubMed=1575724; DOI=10.1016/0006-291X(92)90699-L;
RA Glaemsta E.-L., Meyerson B., Silberring J., Terenius L., Nyberg F.;
RT "Isolation of a hemoglobin-derived opioid peptide from cerebrospinal
RT fluid of patients with cerebrovascular bleedings.";
RL Biochem. Biophys. Res. Commun. 184:1060-1066(1992).
RN [22]
RP PROTEIN SEQUENCE OF 33-42.
RA Ianzer D., Konno K., Xavier C.H., Stoecklin R., Santos R.A.S.,
RA de Camargo A.C.M., Pimenta D.C.;
RL Submitted (JUN-2007) to UniProtKB.
RN [23]
RP PROTEIN SEQUENCE OF 97-121, NUCLEOTIDE SEQUENCE [MRNA] OF 106-113, AND
RP VARIANT BURKE ARG-108.
RX PubMed=8401300;
RA Suzuki H., Wada C., Kamata K., Takahashi E., Sato N., Kunitomo T.;
RT "Globin chain synthesis in hemolytic anemia reticulocytes. A case of
RT hemoglobin Burke.";
RL Biochem. Mol. Biol. Int. 30:425-431(1993).
RN [24]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 122-147.
RX PubMed=2581851; DOI=10.1016/0378-1119(85)90093-9;
RA Lang K.M., Spritz R.A.;
RT "Cloning specific complete polyadenylylated 3'-terminal cDNA
RT segments.";
RL Gene 33:191-196(1985).
RN [25]
RP BISPHOSPHOGLYCERATE BINDING.
RX PubMed=4555506; DOI=10.1038/237146a0;
RA Arnone A.;
RT "X-ray diffraction study of binding of 2,3-diphosphoglycerate to human
RT deoxyhaemoglobin.";
RL Nature 237:146-149(1972).
RN [26]
RP ACETYLATION AT LYS-145.
RX PubMed=4531009; DOI=10.1073/pnas.71.12.4693;
RA Shamsuddin M., Mason R.G., Ritchey J.M., Honig G.R., Klotz I.M.;
RT "Sites of acetylation of sickle cell hemoglobin by aspirin.";
RL Proc. Natl. Acad. Sci. U.S.A. 71:4693-4697(1974).
RN [27]
RP GLYCATION AT VAL-2.
RX PubMed=635569; DOI=10.1126/science.635569;
RA Bunn H.F., Gabbay K.H., Gallop P.M.;
RT "The glycosylation of hemoglobin: relevance to diabetes mellitus.";
RL Science 200:21-27(1978).
RN [28]
RP GLYCATION AT LYS-9; LYS-18; LYS-67; LYS-121 AND LYS-145, AND LACK OF
RP GLYCATION AT LYS-60; LYS-83 AND LYS-96.
RX PubMed=7358733;
RA Shapiro R., McManus M.J., Zalut C., Bunn H.F.;
RT "Sites of nonenzymatic glycosylation of human hemoglobin A.";
RL J. Biol. Chem. 255:3120-3127(1980).
RN [29]
RP INTERACTION WITH HAPTOGLOBIN.
RX PubMed=3718478;
RA Yoshioka N., Atassi M.Z.;
RT "Haemoglobin binding with haptoglobin. Localization of the
RT haptoglobin-binding sites on the beta-chain of human haemoglobin by
RT synthetic overlapping peptides encompassing the entire chain.";
RL Biochem. J. 234:453-456(1986).
RN [30]
RP OXIDATION AT LEU-142.
RX PubMed=1520632; DOI=10.1111/j.1365-2141.1992.tb08179.x;
RA Brennan S.O., Shaw J., Allen J., George P.M.;
RT "Beta 141 Leu is not deleted in the unstable haemoglobin Atlanta-
RT Coventry but is replaced by a novel amino acid of mass 129 daltons.";
RL Br. J. Haematol. 81:99-103(1992).
RN [31]
RP S-NITROSYLATION AT CYS-94.
RX PubMed=8637569; DOI=10.1038/380221a0;
RA Jia L., Bonaventura C., Bonaventura J., Stamler J.S.;
RT "S-nitrosohaemoglobin: a dynamic activity of blood involved in
RT vascular control.";
RL Nature 380:221-226(1996).
RN [32]
RP S-NITROSYLATION AT CYS-94.
RX PubMed=9843411; DOI=10.1021/bi9816711;
RA Chan N.L., Rogers P.H., Arnone A.;
RT "Crystal structure of the S-nitroso form of liganded human
RT hemoglobin.";
RL Biochemistry 37:16459-16464(1998).
RN [33]
RP NITRIC OXIDE-BINDING.
RX PubMed=10588683; DOI=10.1073/pnas.96.25.14206;
RA Durner J., Gow A.J., Stamler J.S., Glazebrook J.;
RT "Ancient origins of nitric oxide signaling in biological systems.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:14206-14207(1999).
RN [34]
RP REVIEW ON FUNCTION OF SPINORPHIN.
RX PubMed=12470213; DOI=10.2174/1389203023380404;
RA Yamamoto Y., Ono H., Ueda A., Shimamura M., Nishimura K., Hazato T.;
RT "Spinorphin as an endogenous inhibitor of enkephalin-degrading
RT enzymes: roles in pain and inflammation.";
RL Curr. Protein Pept. Sci. 3:587-599(2002).
RN [35]
RP SYNTHESIS OF 33-42, AND FUNCTION.
RX PubMed=16904236; DOI=10.1016/j.peptides.2006.06.009;
RA Ianzer D., Konno K., Xavier C.H., Stoecklin R., Santos R.A.S.,
RA de Camargo A.C.M., Pimenta D.C.;
RT "Hemorphin and hemorphin-like peptides isolated from dog pancreas and
RT sheep brain are able to potentiate bradykinin activity in vivo.";
RL Peptides 27:2957-2966(2006).
RN [36]
RP FUNCTION OF SPINORPHIN.
RX PubMed=17676725; DOI=10.1021/jm070114m;
RA Jung K.Y., Moon H.D., Lee G.E., Lim H.H., Park C.S., Kim Y.C.;
RT "Structure-activity relationship studies of spinorphin as a potent and
RT selective human P2X(3) receptor antagonist.";
RL J. Med. Chem. 50:4543-4547(2007).
RN [37]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [38]
RP ELECTRON MICROSCOPY OF SICKLE-CELL HEMOGLOBIN FIBERS.
RX PubMed=4123689; DOI=10.1073/pnas.70.3.718;
RA Finch J.T., Perutz M.F., Bertles J.F., Doebler J.;
RT "Structure of sickled erythrocytes and of sickle-cell hemoglobin
RT fibers.";
RL Proc. Natl. Acad. Sci. U.S.A. 70:718-722(1973).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (5 ANGSTROMS) OF MUTANT VAL-7.
RX PubMed=1195378; DOI=10.1016/S0022-2836(75)80108-2;
RA Wishner B.C., Ward K.B., Lattman E.E., Love W.E.;
RT "Crystal structure of sickle-cell deoxyhemoglobin at 5 A resolution.";
RL J. Mol. Biol. 98:179-194(1975).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF DEOXYHEMOGLOBIN.
RX PubMed=1177322; DOI=10.1016/S0022-2836(75)80037-4;
RA Fermi G.;
RT "Three-dimensional Fourier synthesis of human deoxyhaemoglobin at 2.5-
RT A resolution: refinement of the atomic model.";
RL J. Mol. Biol. 97:237-256(1975).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF CARBONMONOXY HEMOGLOBIN.
RX PubMed=7373648; DOI=10.1016/0022-2836(80)90308-3;
RA Baldwin J.M.;
RT "The structure of human carbonmonoxy haemoglobin at 2.7-A
RT resolution.";
RL J. Mol. Biol. 136:103-128(1980).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.74 ANGSTROMS) OF DEOXYHEMOGLOBIN.
RX PubMed=6726807; DOI=10.1016/0022-2836(84)90472-8;
RA Fermi G., Perutz M.F., Shaanan B., Fourme R.;
RT "The crystal structure of human deoxyhaemoglobin at 1.74 A
RT resolution.";
RL J. Mol. Biol. 175:159-174(1984).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF VARIANT ROTHSCHILD ARG-38.
RX PubMed=1567857; DOI=10.1021/bi00131a030;
RA Kavanaugh J.S., Rogers P.H., Case D.A., Arnone A.;
RT "High-resolution X-ray study of deoxyhemoglobin Rothschild 37 beta
RT Trp-->Arg: a mutation that creates an intersubunit chloride-binding
RT site.";
RL Biochemistry 31:4111-4121(1992).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF MUTANT ARG-75.
RX PubMed=1507231; DOI=10.1016/0022-2836(92)90638-Z;
RA Fermi G., Perutz M.F., Williamson D., Stein P., Shih D.T.;
RT "Structure-function relationships in the low-affinity mutant
RT haemoglobin Aalborg (Gly74 (E18)beta-->Arg).";
RL J. Mol. Biol. 226:883-888(1992).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), AND BISPHOSPHOGLYCERATE
RP BINDING.
RX PubMed=8377203; DOI=10.1006/jmbi.1993.1505;
RA Richard V., Dodson G.G., Mauguen Y.;
RT "Human deoxyhaemoglobin-2,3-diphosphoglycerate complex low-salt
RT structure at 2.5 A resolution.";
RL J. Mol. Biol. 233:270-274(1993).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX PubMed=8642597; DOI=10.1006/jmbi.1996.0124;
RA Paoli M., Liddington R., Tame J., Wilkinson A., Dodson G.;
RT "Crystal structure of T state haemoglobin with oxygen bound at all
RT four haems.";
RL J. Mol. Biol. 256:775-792(1996).
RN [47]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANTS ALA-38; GLU-38;
RP GLY-38 AND TYR-38.
RX PubMed=9521756; DOI=10.1021/bi9708702;
RA Kavanaugh J.S., Weydert J.A., Rogers P.H., Arnone A.;
RT "High-resolution crystal structures of human hemoglobin with mutations
RT at tryptophan 37beta: structural basis for a high-affinity T-state.";
RL Biochemistry 37:4358-4373(1998).
RN [48]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF MUTANT TRP-7.
RX PubMed=9830011; DOI=10.1074/jbc.273.49.32690;
RA Harrington D.J., Adachi K., Royer W.E. Jr.;
RT "Crystal structure of deoxy-human hemoglobin beta6 Glu-->Trp.
RT Implications for the structure and formation of the sickle cell
RT fiber.";
RL J. Biol. Chem. 273:32690-32696(1998).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF MUTANT LYS-7.
RX PubMed=12454462; DOI=10.1107/S0907444902016426;
RA Dewan J.C., Feeling-Taylor A., Puius Y.A., Patskovska L.,
RA Patskovsky Y., Nagel R.L., Almo S.C., Hirsch R.E.;
RT "Structure of mutant human carbonmonoxyhemoglobin C (betaE6K) at 2.0 A
RT resolution.";
RL Acta Crystallogr. D 58:2038-2042(2002).
RN [50]
RP VARIANT FREIBURG VAL-24 DEL.
RX PubMed=5919752; DOI=10.1126/science.154.3752.1024;
RA Jones R.T., Brimhall B., Huisman T.H., Kleihauer E., Betke K.;
RT "Hemoglobin Freiburg: abnormal hemoglobin due to deletion of a single
RT amino acid residue.";
RL Science 154:1024-1027(1966).
RN [51]
RP VARIANT ALABAMA LYS-40.
RX PubMed=1115799;
RA Brimhall B., Jones R.T., Schneider R.G., Hosty T.S., Tomlin G.,
RA Atkins R.;
RT "Two new hemoglobins. Hemoglobin Alabama (beta39(C5)Gln leads to Lys)
RT and hemoglobin Montgomery (alpha 48(CD 6) Leu leads to Arg).";
RL Biochim. Biophys. Acta 379:28-32(1975).
RN [52]
RP INVOLVEMENT IN HEIBAN, AND VARIANT ST LOUIS GLN-29.
RX PubMed=186485; DOI=10.1172/JCI108561;
RA Thillet J., Cohen-Solal M., Seligmann M., Rosa J.;
RT "Functional and physicochemical studies of hemoglobin St. Louis beta
RT 28 (B10) Leu replaced by Gln: a variant with ferric beta heme iron.";
RL J. Clin. Invest. 58:1098-1106(1976).
RN [53]
RP INVOLVEMENT IN B-THALIB.
RX PubMed=1971109; DOI=10.1073/pnas.87.10.3924;
RA Thein S.L., Hesketh C., Taylor P., Temperley I.J., Hutchinson R.M.,
RA Old J.M., Wood W.G., Clegg J.B., Weatherall D.J.;
RT "Molecular basis for dominantly inherited inclusion body beta-
RT thalassemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:3924-3928(1990).
RN [54]
RP VARIANT ALESHA MET-68.
RX PubMed=8330974;
RA Molchanova T.P., Postnikov Y.V., Pobedimskaya D.D., Smetanina N.S.,
RA Moschan A.A., Kazanetz E.G., Tokarev Y.N., Huisman T.H.J.;
RT "Hb Alesha or alpha 2 beta (2)67(E11)Val-->Met: a new unstable
RT hemoglobin variant identified through sequencing of amplified DNA.";
RL Hemoglobin 17:217-225(1993).
RN [55]
RP VARIANT J-ALTGELDS GARDENS ASP-93.
RX PubMed=721609;
RA Adams J.G. III, Przywara K.P., Heller P., Shamsuddin M.;
RT "Hemoglobin J Altgeld Gardens. A hemoglobin variant with a
RT substitution of the proximal histidine of the beta-chain.";
RL Hemoglobin 2:403-415(1978).
RN [56]
RP VARIANT ANKARA ASP-11.
RX PubMed=4850241; DOI=10.1016/0014-5793(74)80766-0;
RA Arcasoy A., Casey R., Lehmann H., Cavdar A.O., Berki A.;
RT "A new haemoglobin J from Turkey -- Hb Ankara (beta10 (A7) Ala-Asp).";
RL FEBS Lett. 42:121-123(1974).
RN [57]
RP VARIANTS J-ANTAKYA MET-66 AND COMPLUTENSE GLU-128.
RX PubMed=3707969; DOI=10.1016/0167-4838(86)90178-0;
RA Huisman T.H.J., Wilson J.B., Kutlar A., Yang K.-G., Chen S.-S.,
RA Webber B.B., Altay C., Martinez A.V.;
RT "Hb J-Antakya or alpha 2 beta (2)65(E9)Lys-->Met in a Turkish family
RT and Hb complutense or alpha 2 beta (2)127(H5)Gln-->Glu in a Spanish
RT family; correction of a previously published identification.";
RL Biochim. Biophys. Acta 871:229-231(1986).
RN [58]
RP VARIANT J-AUCKLAND ASP-26.
RX PubMed=3654265;
RA Williamson D., Wells R.M.G., Anderson R., Matthews J.;
RT "A new unstable and low oxygen affinity hemoglobin variant: Hb J-
RT Auckland [beta 25(B7)Gly-->Asp].";
RL Hemoglobin 11:221-230(1987).
RN [59]
RP VARIANT AURORA TYR-140.
RX PubMed=8718692;
RA Lafferty J., Ali M., Matthew K., Eng B., Patterson M., Waye J.S.;
RT "Identification of a new high oxygen affinity hemoglobin variant: Hb
RT Aurora [beta 139(H17) Asn-->Tyr].";
RL Hemoglobin 19:335-341(1995).
RN [60]
RP VARIANT BREST LYS-128.
RX PubMed=3384710;
RA Baudin-Chich V., Wajcman H., Gombaud-Saintonge G., Arous N., Riou J.,
RA Briere J., Galacteros F.;
RT "Hemoglobin Brest [beta 127 (H5)Gln-->Lys] a new unstable human
RT hemoglobin variant located at the alpha 1 beta 1 interface with
RT specific electrophoretic behavior.";
RL Hemoglobin 12:179-188(1988).
RN [61]
RP VARIANT BRISBANE HIS-69.
RX PubMed=6166590;
RA Brennan S.O., Wells R.M., Smith H., Carrell R.W.;
RT "Hemoglobin Brisbane: beta68 Leu replaced by His. A new high oxygen
RT affinity variant.";
RL Hemoglobin 5:325-335(1981).
RN [62]
RP VARIANT BUNBURY ASN-95.
RX PubMed=6629823;
RA Como P.F., Kennett D., Wilkinson T., Kronenberg H.;
RT "A new hemoglobin with high oxygen affinity -- hemoglobin Bunbury:
RT alpha 2 beta 2 [94 (FG1) Asp replaced by Asn].";
RL Hemoglobin 7:413-421(1983).
RN [63]
RP VARIANT J-CAIRO GLN-66.
RX PubMed=1247583;
RA Garel M.-C., Hassan W., Coquelet M.T., Goossens M., Rosa J., Arous N.;
RT "Hemoglobin J Cairo: beta 65 (E9) Lys leads to Gln, A new hemoglobin
RT variant discovered in an Egyptian family.";
RL Biochim. Biophys. Acta 420:97-104(1976).
RN [64]
RP VARIANT CAMPERDOWN SER-105.
RX PubMed=1138922;
RA Wilkinson T., Chua C.G., Carrell R.W., Robin H., Exner T., Lee K.M.,
RA Kronenberg H.;
RT "A new haemoglobin variant, haemoglobin Camperdown (beta 104 (G6)
RT arginine->serine).";
RL Biochim. Biophys. Acta 393:195-200(1975).
RN [65]
RP VARIANT CARIBBEAN ARG-92.
RX PubMed=992050; DOI=10.1016/0014-5793(76)80662-X;
RA Ahern E., Ahern V., Hilton T., Serjeant G.R., Serjeant B.E.,
RA Seakins M., Lang A., Middleton A., Lehmann H.;
RT "Haemoglobin caribbean beta91 (F7) Leu replaced by Arg: a mildly
RT haemoglobin with a low oxygen affinity.";
RL FEBS Lett. 69:99-102(1976).
RN [66]
RP VARIANT CITY OF HOPE SER-70.
RX PubMed=6434492;
RA Rahbar S., Asmerom Y., Blume K.G.;
RT "A silent hemoglobin variant detected by HPLC: hemoglobin City of Hope
RT beta 69 (E13) Gly-->Ser.";
RL Hemoglobin 8:333-342(1984).
RN [67]
RP VARIANT COIMBRA GLU-100.
RX PubMed=1814856;
RA Tamagnini G.P., Ribeiro M.L., Valente V., Ramachandran M.,
RA Wilson J.B., Baysal E., Gu L.H., Huisman T.H.J.;
RT "Hb Coimbra or alpha 2 beta (2)99(G1)Asp-->Glu, a newly discovered
RT high oxygen affinity variant.";
RL Hemoglobin 15:487-496(1991).
RN [68]
RP VARIANT COSTA RICA ARG-78.
RX PubMed=8641705; DOI=10.1007/s004390050145;
RA Romero W.E.R., Castillo M., Chaves M.A., Saenz G.F., Gu L.-H.,
RA Wilson J.B., Baysal E., Smetanina N.S., Leonova J.Y., Huisman T.H.J.;
RT "Hb Costa Rica or alpha 2 beta 2 77(EF1)His-->Arg: the first example
RT of a somatic cell mutation in a globin gene.";
RL Hum. Genet. 97:829-833(1996).
RN [69]
RP VARIANT DEBROUSSE PRO-97.
RX PubMed=8602627;
RX DOI=10.1002/(SICI)1096-8652(199604)51:4<276::AID-AJH5>3.0.CO;2-T;
RA Lacan P., Kister J., Francina A., Souillet G., Galacteros F.,
RA Delaunay J., Wajcman H.;
RT "Hemoglobin Debrousse (beta 96[FG3]Leu-->Pro): a new unstable
RT hemoglobin with twofold increased oxygen affinity.";
RL Am. J. Hematol. 51:276-281(1996).
RN [70]
RP VARIANT DHONBURI GLY-127.
RX PubMed=2399911; DOI=10.1002/ajh.2830350206;
RA Bardakdjian-Michau J., Fucharoen S., Delanoe-Garin J., Kister J.,
RA Lacombe C., Winichagoon P., Blouquit Y., Riou J., Wasi P.,
RA Galacteros F.;
RT "Hemoglobin Dhonburi alpha 2 beta 2 126 (H4) Val-->Gly: a new unstable
RT beta variant producing a beta-thalassemia intermedia phenotype in
RT association with beta zero-thalassemia.";
RL Am. J. Hematol. 35:96-99(1990).
RN [71]
RP VARIANTS NEWCASTLE PRO-93 AND CAMPERDOWN SER-105, AND DESCRIPTION OF
RP VARIANT DUINO.
RX PubMed=1511986; DOI=10.1007/BF00221961;
RA Wajcman H., Blouquit Y., Vasseur C., le Querrec A., Laniece M.,
RA Melevendi C., Rasore A., Galacteros F.;
RT "Two new human hemoglobin variants caused by unusual mutational
RT events: Hb Zaire contains a five residue repetition within the alpha-
RT chain and Hb Duino has two residues substituted in the beta-chain.";
RL Hum. Genet. 89:676-680(1992).
RN [72]
RP VARIANT DURHAM-N.C. PRO-115.
RX PubMed=1301199; DOI=10.1002/humu.1380010207;
RA Murru S., Poddie D., Sciarratta G.V., Agosti S., Baffico M.,
RA Melevendi C., Pirastu M., Cao A.;
RT "A novel beta-globin structural mutant, Hb Brescia (beta 114 Leu-Pro),
RT causing a severe beta-thalassemia intermedia phenotype.";
RL Hum. Mutat. 1:124-128(1992).
RN [73]
RP VARIANT DURHAM-N.C. PRO-115.
RX PubMed=8111050;
RA de Castro C.M., Devlin B., Fleenor D.E., Lee M.E., Kaufman R.E.;
RT "A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro],
RT produces a dominant thalassemia-like phenotype.";
RL Blood 83:1109-1116(1994).
RN [74]
RP VARIANT J-EUROPA ASP-63.
RX PubMed=8811317;
RA Kiger L., Kister J., Groff P., Kalmes G., Prome D., Galacteros F.,
RA Wajcman H.;
RT "Hb J-Europa [beta 62(E6)Ala-->Asp]: normal oxygen binding properties
RT in a new variant involving a residue located distal to the heme.";
RL Hemoglobin 20:135-140(1996).
RN [75]
RP VARIANT GEELONG ASP-140.
RX PubMed=1917539;
RA Como P.F., Hocking D.R., Swinton G.W., Trent R.J., Holland R.A.B.,
RA Tibben E.A., Wilkinson T., Kronenberg H.;
RT "Hb Geelong [beta 139(H17)Asn-->Asp].";
RL Hemoglobin 15:85-95(1991).
RN [76]
RP VARIANT GRANGE-BLANCHE VAL-28.
RX PubMed=3666141; DOI=10.1016/0014-5793(87)80509-4;
RA Baklouti F., Giraud Y., Francina A., Richard G., Perier C.,
RA Geyssant A., Jaubert J., Brizard C., Delaunay J.;
RT "Hemoglobin Grange-Blanche [beta 27(B9) Ala-->Val], a new variant with
RT normal expression and increased affinity for oxygen.";
RL FEBS Lett. 223:59-62(1987).
RN [77]
RP VARIANT GRAZ LEU-3.
RX PubMed=1487420;
RA Liu J.S., Molchanova T.P., Gu L.H., Wilson J.B., Hopmeier P.,
RA Schnedl W., Balaun E., Krejs G.J., Huisman T.H.J.;
RT "Hb Graz or alpha 2 beta 2(2)(NA2)His-->Leu; a new beta chain variant
RT observed in four families from southern Austria.";
RL Hemoglobin 16:493-501(1992).
RN [78]
RP VARIANT HELSINKI MET-83.
RX PubMed=826083;
RA Ikkala E., Koskela J., Pikkarainen P., Rahiala E.-L., El-Hazmi M.A.F.,
RA Nagai K., Lang A., Lehmann H.;
RT "Hb Helsinki: a variant with a high oxygen affinity and a substitution
RT at a 2,3-DPG binding site (beta82[EF6] Lys replaced by Met).";
RL Acta Haematol. 56:257-275(1976).
RN [79]
RP VARIANT HIMEJI ASP-141.
RX PubMed=3754244;
RA Ohba Y., Miyaji T., Murakami M., Kadowaki S., Fujita T., Oimomi M.,
RA Hatanaka H., Ishikawa K., Baba S., Hitaka K., Imai K.;
RT "Hb Himeji or beta 140 (H18) Ala-->Asp. A slightly unstable hemoglobin
RT with increased beta N-terminal glycation.";
RL Hemoglobin 10:109-126(1986).
RN [80]
RP VARIANT HINSDALE LYS-140.
RX PubMed=2513289;
RA Moo-Penn W.F., Johnson M.H., Jue D.L., Lonser R.;
RT "Hb Hinsdale [beta 139 (H17)Asn-->Lys]: a variant in the central
RT cavity showing reduced affinity for oxygen and 2,3-
RT diphosphoglycerate.";
RL Hemoglobin 13:455-464(1989).
RN [81]
RP VARIANT HINWIL ASN-39.
RX PubMed=8745430;
RA Frischknecht H., Ventruto M., Hess D., Hunziker P., Rosatelli M.C.,
RA Cao A., Breitenstein U., Fehr J., Tuchschmid P.;
RT "HB Hinwil or beta 38(C4)Thr-->Asn: a new beta chain variant detected
RT in a Swiss family.";
RL Hemoglobin 20:31-40(1996).
RN [82]
RP VARIANT HOWICK GLY-38.
RX PubMed=8144352;
RA Owen M.C., Ockelford P.A., Wells R.M.G.;
RT "Hb Howick [beta 37(C3)Trp-->Gly]: a new high oxygen affinity variant
RT of the alpha 1 beta 2 contact.";
RL Hemoglobin 17:513-521(1993).
RN [83]
RP VARIANT INDIANAPOLIS ARG-113.
RX PubMed=429365;
RA Adams J.G. III, Steinberg M.H., Boxer L.A., Baehner R.L., Forget B.G.,
RA Tsistrakis G.A.;
RT "The structure of hemoglobin Indianapolis [beta112(G14) arginine]. An
RT unstable variant detectable only by isotopic labeling.";
RL J. Biol. Chem. 254:3479-3482(1979).
RN [84]
RP VARIANT ISEHARA ASN-93.
RX PubMed=1787097;
RA Harano T., Harano K., Kushida Y., Ueda S., Yoshii A., Nishinarita M.;
RT "Hb Isehara (or Hb Redondo) [beta 92 (F8) His-->Asn]: an unstable
RT variant with a proximal histidine substitution at the heme contact.";
RL Hemoglobin 15:279-290(1991).
RN [85]
RP VARIANT ISTAMBUL GLN-93.
RX PubMed=4639022; DOI=10.1172/JCI107050;
RA Aksoy M., Erdem S., Efremov G.D., Wilson J.B., Huisman T.H.J.,
RA Schroeder W.A., Shelton J.R., Shelton J.B., Ulitin O.N., Muftuoglu A.;
RT "Hemoglobin Istanbul: substitution of glutamine for histidine in a
RT proximal histidine (F8(92)).";
RL J. Clin. Invest. 51:2380-2387(1972).
RN [86]
RP VARIANT JACKSONVILLE ASP-55.
RX PubMed=2101840;
RA Gaudry C.L. Jr., Pitel P.A., Jue D.L., Hine T.K., Johnson M.H.,
RA Moo-Penn W.F.;
RT "Hb Jacksonville [alpha 2 beta 2(54)(D5)Val-->Asp]: a new unstable
RT variant found in a patient with hemolytic anemia.";
RL Hemoglobin 14:653-659(1990).
RN [87]
RP VARIANT JIANGHUA ILE-121.
RX PubMed=6618888;
RA Lu Y.Q., Fan J.L., Liu J.F., Hu H.L., Peng X.H., Huang C.-H.,
RA Huang P.Y., Chen S.S., Jai P.C., Yang K.G.;
RT "Hemoglobin Jianghua [beta 120(GH3) Lys leads to Ile]: a new fast-
RT moving variant found in China.";
RL Hemoglobin 7:321-326(1983).
RN [88]
RP VARIANT KARLSKOGA HIS-22.
RX PubMed=8330972;
RA Landin B.;
RT "Hb Karlskoga or alpha 2 beta (2)21(B3) Asp-->His: a new slow-moving
RT variant found in Sweden.";
RL Hemoglobin 17:201-208(1993).
RN [89]
RP VARIANT KNOSSOS SER-28.
RX PubMed=7173395; DOI=10.1016/0014-5793(82)81052-1;
RA Arous N., Galacteros F., Fessas P., Loukopoulos D., Blouquit Y.,
RA Komis G., Sellaye M., Boussiou M., Rosa J.;
RT "Structural study of hemoglobin Knossos, beta 27 (B9) Ala leads to
RT Ser. A new abnormal hemoglobin present as a silent beta-thalassemia.";
RL FEBS Lett. 147:247-250(1982).
RN [90]
RP VARIANT KODAIRA GLN-147.
RX PubMed=1634367;
RA Harano T., Harano K., Kushida Y., Imai K., Nishinakamura R.,
RA Matsunaga T.;
RT "Hb Kodaira [beta 146(HC3)His-->Gln]: a new beta chain variant with an
RT amino acid substitution at the C-terminus.";
RL Hemoglobin 16:85-91(1992).
RN [91]
RP VARIANT KOFU ILE-85.
RX PubMed=3744871;
RA Harano T., Harano K., Ueda S., Imai N., Kitazumi T.;
RT "A new electrophoretically-silent hemoglobin variant: hemoglobin Kofu
RT or alpha 2 beta 2 84 (EF8) Thr-->Ile.";
RL Hemoglobin 10:417-420(1986).
RN [92]
RP VARIANT HRADEC KRALOVE ASP-116.
RX PubMed=7693620;
RA Divoky V., Svobodova M., Indrak K., Chrobak L., Molchanova T.P.,
RA Huisman T.H.J.;
RT "Hb Hradec Kralove (Hb HK) or alpha 2 beta 2 115(G17)Ala-->Asp, a
RT severely unstable hemoglobin variant resulting in a dominant beta-
RT thalassemia trait in a Czech family.";
RL Hemoglobin 17:319-328(1993).
RN [93]
RP VARIANT LA DESIRADE VAL-130.
RX PubMed=3557994;
RA Merault G., Keclard L., Garin J., Poyart C., Blouquit Y., Arous N.,
RA Galacteros F., Feingold J., Rosa J.;
RT "Hemoglobin La Desirade alpha A2 beta 2 129 (H7) Ala-->Val: a new
RT unstable hemoglobin.";
RL Hemoglobin 10:593-605(1986).
RN [94]
RP VARIANT LA ROCHE-SUR-YON HIS-82.
RX PubMed=1540659; DOI=10.1016/0925-4439(92)90052-O;
RA Wajcman H., Kister J., Vasseur C., Blouquit Y., Trastour J.C.,
RA Cottenceau D., Galacteros F.;
RT "Structure of the EF corner favors deamidation of asparaginyl residues
RT in hemoglobin: the example of Hb La Roche-sur-Yon [beta 81 (EF5)
RT Leu-->His].";
RL Biochim. Biophys. Acta 1138:127-132(1992).
RN [95]
RP VARIANT LAS PALMAS PHE-50.
RX PubMed=3384708;
RA Malcorra-Azpiazu J.J., Balda-Aguirre M.I., Diaz-Chico J.C., Hu H.,
RA Wilson J.B., Webber B.B., Kutlar F., Kutlar A., Huisman T.H.J.;
RT "Hb Las Palmas or alpha 2 beta 2(49)(CD8)Ser-->Phe, a mildly unstable
RT hemoglobin variant.";
RL Hemoglobin 12:163-170(1988).
RN [96]
RP VARIANT LINKOPING THR-37.
RX PubMed=3691763;
RA Berlin G., Wranne B., Jeppsson J.-O.;
RT "Hb Linkoping (beta 36 Pro-->Thr): a new high oxygen affinity
RT hemoglobin variant found in two families of Finnish origin.";
RL Eur. J. Haematol. 39:452-456(1987).
RN [97]
RP VARIANT MAPUTO TYR-48.
RX PubMed=6629824;
RA Marinucci M., Boissel J.P., Massa A., Wajcman H., Tentori L.,
RA Labie D.;
RT "Hemoglobin Maputo: a new beta-chain variant (alpha 2 beta 2 47 (CD6)
RT Asp replaced by Tyr) in combination with hemoglobin S, identified by
RT high performance liquid chromatography (HPLC).";
RL Hemoglobin 7:423-433(1983).
RN [98]
RP VARIANT MATERA LYS-56.
RX PubMed=2384314;
RA Sciarratta G.V., Ivaldi G.;
RT "Hb Matera [beta 55(D6)Met-->Lys]: a new unstable hemoglobin variant
RT in an Italian family.";
RL Hemoglobin 14:79-85(1990).
RN [99]
RP VARIANT MIYASHIRO GLY-24.
RX PubMed=7338468;
RA Nakatsuji T., Miwa S., Ohba Y., Hattori Y., Miyaji T., Miyata H.,
RA Shinohara T., Hori T., Takayama J.;
RT "Hemoglobin Miyashiro (beta 23[B5] val substituting for gly) an
RT electrophoretically silent variant discovered by the isopropanol
RT test.";
RL Hemoglobin 5:653-666(1981).
RN [100]
RP VARIANT MIZUHO PRO-69.
RX PubMed=893142;
RA Ohba Y., Miyaji T., Matsuoka M., Sugiyama K., Suzuki T., Sugiura T.;
RT "Hemoglobin Mizuho or beta 68 (E 12) leucine leads to proline, a new
RT unstable variant associated with severe hemolytic anemia.";
RL Hemoglobin 1:467-477(1977).
RN [101]
RP VARIANT MUSCAT VAL-33.
RX PubMed=1517102;
RA Ramachandran M., Gu L.H., Wilson J.B., Kitundu M.N., Adekile A.D.,
RA Liu J.C., McKie K.M., Huisman T.H.J.;
RT "A new variant, HB Muscat [alpha 2 beta (2)32(B14)Leu-->Val] observed
RT in association with HB S in an Arabian family.";
RL Hemoglobin 16:259-266(1992).
RN [102]
RP VARIANT N-TIMONE GLU-9.
RX PubMed=2634671;
RA Lena-Russo D., Orsini A., Vovan L., Bardakdjian-Michau J., Lacombe C.,
RA Blouquit Y., Craescu C.T., Galacteros F.;
RT "Hb N-Timone [alpha 2 beta 2(8)(A5)Lys-->Glu]: a new fast-moving
RT variant with normal stability and oxygen affinity.";
RL Hemoglobin 13:743-747(1989).
RN [103]
RP VARIANT NAGOYA PRO-98.
RX PubMed=3838976;
RA Ohba Y., Imanaka M., Matsuoka M., Hattori Y., Miyaji T., Funaki C.,
RA Shibata K., Shimokata H., Kuzuya F., Miwa S.;
RT "A new unstable, high oxygen affinity hemoglobin: Hb Nagoya or beta 97
RT (FG4) His-->Pro.";
RL Hemoglobin 9:11-24(1985).
RN [104]
RP VARIANT D-NEATH ALA-122.
RX PubMed=8330979;
RA Welch S.G., Bateman C.;
RT "Hb D-Neath or beta 121 (GH4) Glu-->Ala: a new member of the Hb D
RT family.";
RL Hemoglobin 17:255-259(1993).
RN [105]
RP VARIANT NORTH CHICAGO SER-37.
RX PubMed=3937824;
RA Rahbar S., Louis J., Lee T., Asmerom Y.;
RT "Hemoglobin North Chicago (beta 36 [C2] proline-->serine): a new high
RT affinity hemoglobin.";
RL Hemoglobin 9:559-576(1985).
RN [106]
RP VARIANT NORTH SHORE-CARACAS GLU-135.
RX PubMed=891976; DOI=10.1016/0014-5793(77)80453-5;
RA Arends T., Lehmann H., Plowman D., Stathopoulou R.;
RT "Haemoglobin North Shore-Caracas beta 134 (H12) valine replaced by
RT glutamic acid.";
RL FEBS Lett. 80:261-265(1977).
RN [107]
RP VARIANT OLOMOUC ASP-87.
RX PubMed=3623975;
RA Indrak K., Wiedermann B.F., Batek F., Wilson J.B., Webber B.B.,
RA Kutlar A., Huisman T.H.J.;
RT "Hb Olomouc or alpha 2 beta 2(86)(F2)Ala-->Asp, a new high oxygen
RT affinity variant.";
RL Hemoglobin 11:151-155(1987).
RN [108]
RP VARIANT PALMERSTON NORTH PHE-24.
RX PubMed=7161106;
RA Brennan S.O., Williamson D., Whisson M.E., Carrell R.W.;
RT "Hemoglobin Palmerston North beta 23 (B5) Val replaced by Phe. A new
RT variant identified in a patient with polycythemia.";
RL Hemoglobin 6:569-575(1982).
RN [109]
RP VARIANT PIERRE-BENITE ASP-91.
RX PubMed=3384709;
RA Baklouti F., Giraud Y., Francina A., Richard G., Favre-Gilly J.,
RA Delaunay J.;
RT "Hemoglobin Pierre-Benite [beta 90(F6)Glu-->Asp], a new high affinity
RT variant found in a French family.";
RL Hemoglobin 12:171-177(1988).
RN [110]
RP VARIANT PRESBYTERIAN LYS-109.
RX PubMed=668922; DOI=10.1016/0014-5793(78)80720-0;
RA Moo-Penn W.F., Wolff J.A., Simon G., Vacek M., Jue D.L., Johnson M.H.;
RT "Hemoglobin Presbyterian: beta108 (G10) asparagine leads to lysine, A
RT hemoglobin variant with low oxygen affinity.";
RL FEBS Lett. 92:53-56(1978).
RN [111]
RP VARIANT PUTTELANGE VAL-141.
RX PubMed=8522332; DOI=10.1007/BF00210304;
RA Wajcman H., Girodon E., Prome D., North M.L., Plassa F., Duwig I.,
RA Kister J., Bergerat J.P., Oberling F., Lampert E., Lonsdorfer J.,
RA Goossens M., Galacteros F.;
RT "Germline mosaicism for an alanine to valine substitution at residue
RT beta 140 in hemoglobin Puttelange, a new variant with high oxygen
RT affinity.";
RL Hum. Genet. 96:711-716(1995).
RN [112]
RP VARIANT QUIN-HAI ARG-79.
RX PubMed=6629822;
RA Jen P.C., Chen L.C., Chen P.F., Wong Y., Chen L.F., Guo Y.Y.,
RA Chang F.Q., Chow Y.C., Chiu Y.;
RT "Hemoglobin Quin-Hai, beta 78 (EF2) Leu replaced by Arg, a new
RT abnormal hemoglobin found in Guangdong, China.";
RL Hemoglobin 7:407-412(1983).
RN [113]
RP VARIANT RAMBAM ASP-70.
RX PubMed=9761252;
RA Bisse E., Zorn N., Eigel A., Lizama M., Huamam-Guillen P., Marz W.,
RA van Dorsselaer A., Wieland H.;
RT "Hemoglobin Rambam (beta69[E13]Gly-->Asp), a pitfall in the assessment
RT of diabetic control: characterization by electrospray mass
RT spectrometry and HPLC.";
RL Clin. Chem. 44:2172-2177(1998).
RN [114]
RP VARIANT RANDWICK GLY-16.
RX PubMed=3384707;
RA Gilbert A.T., Fleming P.J., Sumner D.R., Hughes W.G., Ip F.,
RA Kwan Y.L., Holland R.A.B.;
RT "Hemoglobin Randwick or beta 15 (A12)Trp-->Gly: a new unstable beta-
RT chain hemoglobin variant.";
RL Hemoglobin 12:149-161(1988).
RN [115]
RP VARIANT RIO GRANDE THR-9.
RX PubMed=6857757;
RA Moo-Penn W.F., Johnson M.H., McGuffey J.E., Jue D.L.,
RA Therrell B.L. Jr.;
RT "Hemoglobin Rio Grande [beta 8 (A5) Lys leads to Thr] a new variant
RT found in a Mexican-American family.";
RL Hemoglobin 7:91-95(1983).
RN [116]
RP VARIANT RUSH GLN-102.
RX PubMed=4129558;
RA Adams J.G. III, Winter W.P., Tausk K., Heller P.;
RT "Hemoglobin Rush (beta 101 (g3) glutamine): a new unstable hemoglobin
RT causing mild hemolytic anemia.";
RL Blood 43:261-269(1974).
RN [117]
RP VARIANT SAITAMA PRO-118.
RX PubMed=6687721;
RA Ohba Y., Hasegawa Y., Amino H., Miwa S., Nakatsuji T., Hattori Y.,
RA Miyaji T.;
RT "Hemoglobin Saitama or beta 117 (G19) His leads to Pro, a new variant
RT causing hemolytic disease.";
RL Hemoglobin 7:47-56(1983).
RN [118]
RP VARIANT M-SASKATOON TYR-64.
RX PubMed=13897827; DOI=10.1073/pnas.47.11.1758;
RA Gerald P.S., Efron M.L.;
RT "Chemical studies of several varieties of Hb M.";
RL Proc. Natl. Acad. Sci. U.S.A. 47:1758-1767(1961).
RN [119]
RP VARIANT SHELBY/LESLIE/DEACONESS LYS-132.
RX PubMed=6526653;
RA Moo-Penn W.F., Johnson M.H., McGuffey J.E., Jue D.L.;
RT "Hemoglobin Shelby [beta 131(H9) Gln-->Lys] a correction to the
RT structure of hemoglobin Deaconess and hemoglobin Leslie.";
RL Hemoglobin 8:583-593(1984).
RN [120]
RP VARIANT J-SICILIA ASN-66.
RX PubMed=4852224; DOI=10.1016/0014-5793(74)80050-5;
RA Ricco G., Pich P.G., Mazza U., Rossi G., Ajmar P., Arese P., Gallo E.;
RT "Hb J Sicilia: beta 65 (E9) Lys-Asn, a beta homologue of Hb Zambia.";
RL FEBS Lett. 39:200-204(1974).
RN [121]
RP VARIANT STANMORE ALA-112.
RX PubMed=1917537;
RA Como P.F., Wylie B.R., Trent R.J., Bruce D., Volpato F., Wilkinson T.,
RA Kronenberg H., Holland R.A.B., Tibben E.A.;
RT "A new unstable and low oxygen affinity hemoglobin variant: Hb
RT Stanmore [beta 111(G13)Val-->Ala].";
RL Hemoglobin 15:53-65(1991).
RN [122]
RP VARIANT ST MANDE TYR-103.
RX PubMed=7238856; DOI=10.1016/0014-5793(81)81046-0;
RA Arous N., Braconnier F., Thillet J., Blouquit Y., Galacteros F.,
RA Chevrier M., Bordahandy C., Rosa J.;
RT "Hemoglobin Saint Mande beta 102 (G4) asn replaced by tyr: a new low
RT oxygen affinity variant.";
RL FEBS Lett. 126:114-116(1981).
RN [123]
RP VARIANT WINDSOR ASP-12.
RX PubMed=2599880;
RA Gilbert A.T., Fleming P.J., Sumner D.R., Hughes W.G., Holland R.A.B.,
RA Tibben E.A.;
RT "Hemoglobin Windsor or beta 11 (A8)Val-->Asp: a new unstable beta-
RT chain hemoglobin variant producing a hemolytic anemia.";
RL Hemoglobin 13:437-453(1989).
RN [124]
RP VARIANT YAHATA TYR-113.
RX PubMed=1917530;
RA Harano T., Harano K., Kushida Y., Ueda S.;
RT "A new abnormal variant, Hb Yahata or beta 112(G14)Cys-->Tyr, found in
RT a Japanese: structural confirmation by DNA sequencing of the beta-
RT globin gene.";
RL Hemoglobin 15:109-113(1991).
RN [125]
RP VARIANT YOKOHAMA PRO-32.
RX PubMed=7338469;
RA Nakatsuji T., Miwa S., Ohba Y., Hattori Y., Miyaji T., Hino S.,
RA Matsumoto N.;
RT "A new unstable hemoglobin, Hb Yokohama beta 31 (B13)Leu substituting
RT for Pro, causing hemolytic anemia.";
RL Hemoglobin 5:667-678(1981).
RN [126]
RP INVOLVEMENT IN HEIBAN, AND VARIANT HAMMERSMITH SER-43.
RX PubMed=6259091;
RA Rahbar S., Feagler R.J., Beutler E.;
RT "Hemoglobin Hammersmith (beta 42 (CD1) Phe replaced by Ser) associated
RT with severe hemolytic anemia.";
RL Hemoglobin 5:97-105(1981).
RN [127]
RP INVOLVEMENT IN HEIBAN, AND VARIANTS BRUXELLES PHE-42 DEL AND PHE-43
RP DEL.
RX PubMed=2599881;
RA Blouquit Y., Bardakdjian J., Lena-Russo D., Arous N., Perrimond H.,
RA Orsini A., Rosa J., Galacteros F.;
RT "Hb Bruxelles: alpha 2A beta (2)41 or 42(C7 or CD1)Phe deleted.";
RL Hemoglobin 13:465-474(1989).
RN [128]
RP VARIANT ZENGCHENG MET-115.
RX PubMed=2079435;
RA Plaseska D., Wilson J.B., Gu L.H., Kutlar F., Huisman T.H.J.,
RA Zeng Y.T., Shen M.;
RT "Hb Zengcheng or alpha 2 beta(2)114(G16)Leu-->Met.";
RL Hemoglobin 14:555-557(1990).
RN [129]
RP VARIANT NON-SPHEROCYTIC HAEMOLITIC ANEMIA GLY-68.
RX PubMed=8280608; DOI=10.1111/j.1365-2141.1993.tb03178.x;
RA Fay K.C., Brennan S.O., Costello J.M., Potter H.C., Williamson D.A.,
RA Trent R.J., Ockelford P.A., Boswell D.R.;
RT "Haemoglobin Manukau beta 67[E11] Val-->Gly: transfusion-dependent
RT haemolytic anaemia ameliorated by coexisting alpha thalassaemia.";
RL Br. J. Haematol. 85:352-355(1993).
RN [130]
RP INVOLVEMENT IN HEIBAN, AND VARIANT BRISTOL ASP-68.
RX PubMed=8704193;
RA Rees D.C., Rochette J., Schofield C., Green B., Morris M.,
RA Parker N.E., Sasaki H., Tanaka A., Ohba Y., Clegg J.B.;
RT "A novel silent posttranslational mechanism converts methionine to
RT aspartate in hemoglobin Bristol (beta 67[E11] Val-Met->Asp).";
RL Blood 88:341-348(1996).
RN [131]
RP VARIANT IRAQ-HALABJA VAL-11.
RX PubMed=10398311;
RX DOI=10.1002/(SICI)1096-8652(199907)61:3<187::AID-AJH5>3.0.CO;2-7;
RA Deutsch S., Darbellay R., Offord R.E., Frutiger A., Kister J.,
RA Wajcman H., Beris P.;
RT "Hb Iraq-Halabja beta10 (A7) Ala-->Val (GCC-->GTC): a new beta-chain
RT silent variant in a family with multiple Hb disorders.";
RL Am. J. Hematol. 61:187-193(1999).
RN [132]
RP VARIANT VILLEJUIF ILE-124.
RX PubMed=11300351; DOI=10.1081/HEM-100103071;
RA Carbone V., Salzano A.M., Pagano L., Buffardi S., De Rosa C.,
RA Pucci P.;
RT "Identification of Hb Villejuif [beta123(H1)Thr-->Ile] in Southern
RT Italy.";
RL Hemoglobin 25:67-78(2001).
RN [133]
RP VARIANT TSUKUMI TYR-118.
RX PubMed=11300344; DOI=10.1081/HEM-100103076;
RA North M.L., Duwig I., Riou J., Prome D., Yapo A.P., Kister J.,
RA Bardakdjian-Michau J., Cazenave J.-P., Wajcman H.;
RT "Hb Tsukumi [beta117(G19)His-->Tyr] found in a Moroccan woman.";
RL Hemoglobin 25:107-110(2001).
RN [134]
RP VARIANT CANTERBURY PHE-113.
RX PubMed=11939514; DOI=10.1081/HEM-120002942;
RA Brennan S.O., Potter H.C., Kubala L.M., Carnoutsos S.A.,
RA Ferguson M.M.;
RT "Hb Canterbury [beta112(G14)Cys-->Phe]: a new, mildly unstable
RT variant.";
RL Hemoglobin 26:67-69(2002).
RN [135]
RP VARIANT PYRGOS ASP-84, AND VARIANT E LYS-27.
RX PubMed=12144064; DOI=10.1081/HEM-120005459;
RA Sawangareetrakul P., Svasti S., Yodsowon B., Winichagoon P.,
RA Srisomsap C., Svasti J., Fucharoen S.;
RT "Double heterozygosity for Hb Pyrgos [beta83(EF7)Gly-->Asp] and Hb E
RT [beta26(B8)Glu-->Lys] found in association with alpha-thalassemia.";
RL Hemoglobin 26:191-196(2002).
RN [136]
RP VARIANT SANTANDER ASP-35.
RX PubMed=12603091; DOI=10.1081/HEM-120016378;
RA Villegas A., Ropero P., Nogales A., Gonzalez F.A., Mateo M., Mazo E.,
RA Rodrigo E., Arias M.;
RT "Hb Santander [beta34(B16)Val-->Asp (GTC-->GAC)]: a new unstable
RT variant found as a de novo mutation in a Spanish patient.";
RL Hemoglobin 27:31-35(2003).
RN [137]
RP VARIANT NANTES LEU-35, AND VARIANT VEXIN LEU-117.
RX PubMed=12908805; DOI=10.1081/HEM-120023384;
RA Wajcman H., Bardakdjian-Michau J., Riou J., Prehu C., Kister J.,
RA Baudin-Creuza V., Prome D., Richelme-David S., Harousseau J.L.,
RA Galacteros F.;
RT "Two new hemoglobin variants with increased oxygen affinity: Hb Nantes
RT [beta34(B16)Val-->Leu] and Hb Vexin [beta116(G18)His-->Leu].";
RL Hemoglobin 27:191-199(2003).
RN [138]
RP VARIANT LYS-27.
RX PubMed=15481886; DOI=10.1081/HEM-120040334;
RA Flatz G., Sanguansermsri T., Sengchanh S., Horst D., Horst J.;
RT "The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-
RT globin anomalies in the Lao Theung population of southern Laos.";
RL Hemoglobin 28:197-204(2004).
CC -!- FUNCTION: Involved in oxygen transport from the lung to the
CC various peripheral tissues.
CC -!- FUNCTION: LVV-hemorphin-7 potentiates the activity of bradykinin,
CC causing a decrease in blood pressure.
CC -!- FUNCTION: Spinorphin: functions as an endogenous inhibitor of
CC enkephalin-degrading enzymes such as DPP3, and as a selective
CC antagonist of the P2RX3 receptor which is involved in pain
CC signaling, these properties implicate it as a regulator of pain
CC and inflammation.
CC -!- SUBUNIT: Heterotetramer of two alpha chains and two beta chains in
CC adult hemoglobin A (HbA).
CC -!- INTERACTION:
CC P69905:HBA2; NbExp=19; IntAct=EBI-715554, EBI-714680;
CC -!- TISSUE SPECIFICITY: Red blood cells.
CC -!- PTM: Glucose reacts non-enzymatically with the N-terminus of the
CC beta chain to form a stable ketoamine linkage. This takes place
CC slowly and continuously throughout the 120-day life span of the
CC red blood cell. The rate of glycation is increased in patients
CC with diabetes mellitus.
CC -!- PTM: S-nitrosylated; a nitric oxide group is first bound to Fe(2+)
CC and then transferred to Cys-94 to allow capture of O(2).
CC -!- PTM: Acetylated on Lys-60, Lys-83 and Lys-145 upon aspirin
CC exposure. PubMed:16916647 reports the identification of HBB
CC acetylated on Lys-145 in the cytosolic fraction of HeLa cells.
CC This may have resulted from contamination of the sample.
CC -!- MASS SPECTROMETRY: Mass=1310; Method=FAB; Range=33-42;
CC Source=PubMed:1575724;
CC -!- DISEASE: Heinz body anemias (HEIBAN) [MIM:140700]: Form of non-
CC spherocytic hemolytic anemia of Dacie type 1. After splenectomy,
CC which has little benefit, basophilic inclusions called Heinz
CC bodies are demonstrable in the erythrocytes. Before splenectomy,
CC diffuse or punctate basophilia may be evident. Most of these cases
CC are probably instances of hemoglobinopathy. The hemoglobin
CC demonstrates heat lability. Heinz bodies are observed also with
CC the Ivemark syndrome (asplenia with cardiovascular anomalies) and
CC with glutathione peroxidase deficiency. Note=The disease may be
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Beta-thalassemia (B-THAL) [MIM:613985]: A form of
CC thalassemia. Thalassemias are common monogenic diseases occurring
CC mostly in Mediterranean and Southeast Asian populations. The
CC hallmark of beta-thalassemia is an imbalance in globin-chain
CC production in the adult HbA molecule. Absence of beta chain causes
CC beta(0)-thalassemia, while reduced amounts of detectable beta
CC globin causes beta(+)-thalassemia. In the severe forms of beta-
CC thalassemia, the excess alpha globin chains accumulate in the
CC developing erythroid precursors in the marrow. Their deposition
CC leads to a vast increase in erythroid apoptosis that in turn
CC causes ineffective erythropoiesis and severe microcytic
CC hypochromic anemia. Clinically, beta-thalassemia is divided into
CC thalassemia major which is transfusion dependent, thalassemia
CC intermedia (of intermediate severity), and thalassemia minor that
CC is asymptomatic. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Sickle cell anemia (SKCA) [MIM:603903]: Characterized by
CC abnormally shaped red cells resulting in chronic anemia and
CC periodic episodes of pain, serious infections and damage to vital
CC organs. Normal red blood cells are round and flexible and flow
CC easily through blood vessels, but in sickle cell anemia, the
CC abnormal hemoglobin (called Hb S) causes red blood cells to become
CC stiff. They are C-shaped and resembles a sickle. These stiffer red
CC blood cells can led to microvascular occlusion thus cutting off
CC the blood supply to nearby tissues. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Beta-thalassemia, dominant, inclusion body type (B-
CC THALIB) [MIM:603902]: An autosomal dominant form of beta
CC thalassemia characterized by moderate anemia, lifelong jaundice,
CC cholelithiasis and splenomegaly, marked morphologic changes in the
CC red cells, erythroid hyperplasia of the bone marrow with increased
CC numbers of multinucleate red cell precursors, and the presence of
CC large inclusion bodies in the normoblasts, both in the marrow and
CC in the peripheral blood after splenectomy. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: One molecule of 2,3-bisphosphoglycerate can bind to
CC two beta chains per hemoglobin tetramer.
CC -!- SIMILARITY: Belongs to the globin family.
CC -!- WEB RESOURCE: Name=HbVar; Note=Human hemoglobin variants and
CC thalassemias;
CC URL="http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=directlink&gene;=HBB";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HBB";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=HBB";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hemoglobin entry;
CC URL="http://en.wikipedia.org/wiki/Hemoglobin";
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DR EMBL; M25079; AAA35597.1; -; mRNA.
DR EMBL; V00499; CAA23758.1; -; Genomic_DNA.
DR EMBL; DQ126270; AAZ39745.1; -; Genomic_DNA.
DR EMBL; DQ126271; AAZ39746.1; -; Genomic_DNA.
DR EMBL; DQ126272; AAZ39747.1; -; Genomic_DNA.
DR EMBL; DQ126273; AAZ39748.1; -; Genomic_DNA.
DR EMBL; DQ126274; AAZ39749.1; -; Genomic_DNA.
DR EMBL; DQ126275; AAZ39750.1; -; Genomic_DNA.
DR EMBL; DQ126276; AAZ39751.1; -; Genomic_DNA.
DR EMBL; DQ126277; AAZ39752.1; -; Genomic_DNA.
DR EMBL; DQ126278; AAZ39753.1; -; Genomic_DNA.
DR EMBL; DQ126279; AAZ39754.1; -; Genomic_DNA.
DR EMBL; DQ126280; AAZ39755.1; -; Genomic_DNA.
DR EMBL; DQ126281; AAZ39756.1; -; Genomic_DNA.
DR EMBL; DQ126282; AAZ39757.1; -; Genomic_DNA.
DR EMBL; DQ126283; AAZ39758.1; -; Genomic_DNA.
DR EMBL; DQ126284; AAZ39759.1; -; Genomic_DNA.
DR EMBL; DQ126285; AAZ39760.1; -; Genomic_DNA.
DR EMBL; DQ126286; AAZ39761.1; -; Genomic_DNA.
DR EMBL; DQ126287; AAZ39762.1; -; Genomic_DNA.
DR EMBL; DQ126288; AAZ39763.1; -; Genomic_DNA.
DR EMBL; DQ126289; AAZ39764.1; -; Genomic_DNA.
DR EMBL; DQ126290; AAZ39765.1; -; Genomic_DNA.
DR EMBL; DQ126291; AAZ39766.1; -; Genomic_DNA.
DR EMBL; DQ126292; AAZ39767.1; -; Genomic_DNA.
DR EMBL; DQ126293; AAZ39768.1; -; Genomic_DNA.
DR EMBL; DQ126294; AAZ39769.1; -; Genomic_DNA.
DR EMBL; DQ126295; AAZ39770.1; -; Genomic_DNA.
DR EMBL; DQ126296; AAZ39771.1; -; Genomic_DNA.
DR EMBL; DQ126297; AAZ39772.1; -; Genomic_DNA.
DR EMBL; DQ126298; AAZ39773.1; -; Genomic_DNA.
DR EMBL; DQ126299; AAZ39774.1; -; Genomic_DNA.
DR EMBL; DQ126300; AAZ39775.1; -; Genomic_DNA.
DR EMBL; DQ126301; AAZ39776.1; -; Genomic_DNA.
DR EMBL; DQ126302; AAZ39777.1; -; Genomic_DNA.
DR EMBL; DQ126303; AAZ39778.1; -; Genomic_DNA.
DR EMBL; DQ126304; AAZ39779.1; -; Genomic_DNA.
DR EMBL; DQ126305; AAZ39780.1; -; Genomic_DNA.
DR EMBL; DQ126306; AAZ39781.1; -; Genomic_DNA.
DR EMBL; DQ126307; AAZ39782.1; -; Genomic_DNA.
DR EMBL; DQ126308; AAZ39783.1; -; Genomic_DNA.
DR EMBL; DQ126309; AAZ39784.1; -; Genomic_DNA.
DR EMBL; DQ126310; AAZ39785.1; -; Genomic_DNA.
DR EMBL; DQ126311; AAZ39786.1; -; Genomic_DNA.
DR EMBL; DQ126312; AAZ39787.1; -; Genomic_DNA.
DR EMBL; DQ126313; AAZ39788.1; -; Genomic_DNA.
DR EMBL; DQ126314; AAZ39789.1; -; Genomic_DNA.
DR EMBL; DQ126315; AAZ39790.1; -; Genomic_DNA.
DR EMBL; DQ126316; AAZ39791.1; -; Genomic_DNA.
DR EMBL; DQ126317; AAZ39792.1; -; Genomic_DNA.
DR EMBL; DQ126318; AAZ39793.1; -; Genomic_DNA.
DR EMBL; DQ126319; AAZ39794.1; -; Genomic_DNA.
DR EMBL; DQ126320; AAZ39795.1; -; Genomic_DNA.
DR EMBL; DQ126321; AAZ39796.1; -; Genomic_DNA.
DR EMBL; DQ126322; AAZ39797.1; -; Genomic_DNA.
DR EMBL; DQ126323; AAZ39798.1; -; Genomic_DNA.
DR EMBL; DQ126324; AAZ39799.1; -; Genomic_DNA.
DR EMBL; DQ126325; AAZ39800.1; -; Genomic_DNA.
DR EMBL; AF007546; AAB62944.1; -; Genomic_DNA.
DR EMBL; AF083883; AAL68978.1; -; Genomic_DNA.
DR EMBL; AF117710; AAD19696.1; -; mRNA.
DR EMBL; AF181989; AAF00489.1; -; mRNA.
DR EMBL; AF349114; AAK29639.1; -; mRNA.
DR EMBL; AF527577; AAM92001.1; -; Genomic_DNA.
DR EMBL; AY136510; AAN11320.1; -; mRNA.
DR EMBL; AY163866; AAN84548.1; -; Genomic_DNA.
DR EMBL; AY260740; AAP21062.1; -; Genomic_DNA.
DR EMBL; AY509193; AAR96398.1; -; mRNA.
DR EMBL; EF450778; ABO36678.1; -; Genomic_DNA.
DR EMBL; EU694432; ACD39349.1; -; mRNA.
DR EMBL; AK311825; BAG34767.1; -; mRNA.
DR EMBL; CR536530; CAG38767.1; -; mRNA.
DR EMBL; CR541913; CAG46711.1; -; mRNA.
DR EMBL; CH471064; EAW68806.1; -; Genomic_DNA.
DR EMBL; BC007075; AAH07075.1; -; mRNA.
DR EMBL; U01317; AAA16334.1; -; Genomic_DNA.
DR EMBL; V00497; CAA23756.1; -; mRNA.
DR EMBL; V00500; CAA23759.1; ALT_SEQ; mRNA.
DR EMBL; L26462; AAA21100.1; -; Genomic_DNA.
DR EMBL; L26463; AAA21101.1; -; Genomic_DNA.
DR EMBL; L26464; AAA21102.1; -; Genomic_DNA.
DR EMBL; L26465; AAA21103.1; -; Genomic_DNA.
DR EMBL; L26466; AAA21104.1; -; Genomic_DNA.
DR EMBL; L26467; AAA21105.1; -; Genomic_DNA.
DR EMBL; L26468; AAA21106.1; -; Genomic_DNA.
DR EMBL; L26469; AAA21107.1; -; Genomic_DNA.
DR EMBL; L26470; AAA21108.1; -; Genomic_DNA.
DR EMBL; L26471; AAA21109.1; -; Genomic_DNA.
DR EMBL; L26472; AAA21110.1; -; Genomic_DNA.
DR EMBL; L26473; AAA21111.1; -; Genomic_DNA.
DR EMBL; L26474; AAA21112.1; -; Genomic_DNA.
DR EMBL; L26475; AAA21113.1; -; Genomic_DNA.
DR EMBL; L26476; AAA21114.1; -; Genomic_DNA.
DR EMBL; L26477; AAA21115.1; -; Genomic_DNA.
DR EMBL; L26478; AAA21116.1; -; Genomic_DNA.
DR EMBL; L48213; AAA88063.1; -; Genomic_DNA.
DR EMBL; L48214; AAA88061.1; -; Genomic_DNA.
DR EMBL; L48215; AAA88059.1; -; Genomic_DNA.
DR EMBL; L48216; AAA88065.1; -; Genomic_DNA.
DR EMBL; L48217; AAA88067.1; -; Genomic_DNA.
DR EMBL; M36640; AAA52634.1; -; Genomic_DNA.
DR EMBL; M11428; AAA52633.1; -; mRNA.
DR EMBL; M25113; AAA35966.1; -; mRNA.
DR EMBL; L48932; AAA88054.1; -; Genomic_DNA.
DR PIR; A53136; HBHU.
DR RefSeq; NP_000509.1; NM_000518.4.
DR UniGene; Hs.523443; -.
DR PDB; 1A00; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1A01; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1A0U; X-ray; 2.14 A; B/D=3-147.
DR PDB; 1A0Z; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1A3N; X-ray; 1.80 A; B/D=2-147.
DR PDB; 1A3O; X-ray; 1.80 A; B/D=2-147.
DR PDB; 1ABW; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1ABY; X-ray; 2.60 A; B/D=3-147.
DR PDB; 1AJ9; X-ray; 2.20 A; B=2-147.
DR PDB; 1B86; X-ray; 2.50 A; B/D=2-147.
DR PDB; 1BAB; X-ray; 1.50 A; B/D=2-147.
DR PDB; 1BBB; X-ray; 1.70 A; B/D=2-147.
DR PDB; 1BIJ; X-ray; 2.30 A; B/D=2-147.
DR PDB; 1BUW; X-ray; 1.90 A; B/D=2-147.
DR PDB; 1BZ0; X-ray; 1.50 A; B/D=2-147.
DR PDB; 1BZ1; X-ray; 1.59 A; B/D=2-147.
DR PDB; 1BZZ; X-ray; 1.59 A; B/D=2-147.
DR PDB; 1C7B; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1C7C; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1C7D; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1CBL; X-ray; 1.80 A; A/B/C/D=2-147.
DR PDB; 1CBM; X-ray; 1.74 A; A/B/C/D=1-147.
DR PDB; 1CH4; X-ray; 2.50 A; A/B/C/D=2-107.
DR PDB; 1CLS; X-ray; 1.90 A; B/D=1-147.
DR PDB; 1CMY; X-ray; 3.00 A; B/D=1-147.
DR PDB; 1COH; X-ray; 2.90 A; B/D=1-147.
DR PDB; 1DKE; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1DXT; X-ray; 1.70 A; B/D=1-147.
DR PDB; 1DXU; X-ray; 1.70 A; B/D=3-147.
DR PDB; 1DXV; X-ray; 1.70 A; B/D=3-147.
DR PDB; 1FN3; X-ray; 2.48 A; B/D=2-147.
DR PDB; 1G9V; X-ray; 1.85 A; B/D=2-147.
DR PDB; 1GBU; X-ray; 1.80 A; B/D=2-147.
DR PDB; 1GBV; X-ray; 2.00 A; B/D=2-147.
DR PDB; 1GLI; X-ray; 2.50 A; B/D=3-147.
DR PDB; 1GZX; X-ray; 2.10 A; B/D=2-147.
DR PDB; 1HAB; X-ray; 2.30 A; B/D=2-146.
DR PDB; 1HAC; X-ray; 2.60 A; B/D=2-146.
DR PDB; 1HBA; X-ray; 2.10 A; B/D=2-147.
DR PDB; 1HBB; X-ray; 1.90 A; B/D=2-147.
DR PDB; 1HBS; X-ray; 3.00 A; B/D/F/H=1-147.
DR PDB; 1HCO; X-ray; 2.70 A; B=2-147.
DR PDB; 1HDB; X-ray; 2.20 A; B/D=1-147.
DR PDB; 1HGA; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1HGB; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1HGC; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1HHO; X-ray; 2.10 A; B=1-147.
DR PDB; 1IRD; X-ray; 1.25 A; B=1-147.
DR PDB; 1J3Y; X-ray; 1.55 A; B/D/F/H=1-147.
DR PDB; 1J3Z; X-ray; 1.60 A; B/D/F/H=1-147.
DR PDB; 1J40; X-ray; 1.45 A; B/D/F/H=1-147.
DR PDB; 1J41; X-ray; 1.45 A; B/D/F/H=1-147.
DR PDB; 1J7S; X-ray; 2.20 A; B/D=3-147.
DR PDB; 1J7W; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1J7Y; X-ray; 1.70 A; B/D=3-147.
DR PDB; 1JY7; X-ray; 3.20 A; B/D/Q/S/V/X=1-147.
DR PDB; 1K0Y; X-ray; 1.87 A; B/D=1-147.
DR PDB; 1K1K; X-ray; 2.00 A; B=1-147.
DR PDB; 1KD2; X-ray; 1.87 A; B/D=1-147.
DR PDB; 1LFL; X-ray; 2.70 A; B/D/Q/S=1-147.
DR PDB; 1LFQ; X-ray; 2.60 A; B=1-147.
DR PDB; 1LFT; X-ray; 2.60 A; B=1-147.
DR PDB; 1LFV; X-ray; 2.80 A; B=1-147.
DR PDB; 1LFY; X-ray; 3.30 A; B=1-147.
DR PDB; 1LFZ; X-ray; 3.10 A; B=1-147.
DR PDB; 1LJW; X-ray; 2.16 A; B=1-147.
DR PDB; 1M9P; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1MKO; X-ray; 2.18 A; B/D=1-147.
DR PDB; 1NEJ; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1NIH; X-ray; 2.60 A; B/D=1-147.
DR PDB; 1NQP; X-ray; 1.73 A; B/D=1-147.
DR PDB; 1O1I; X-ray; 2.30 A; B=1-147.
DR PDB; 1O1J; X-ray; 1.90 A; B/D=1-147.
DR PDB; 1O1K; X-ray; 2.00 A; B/D=1-147.
DR PDB; 1O1L; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1O1M; X-ray; 1.85 A; B/D=1-147.
DR PDB; 1O1N; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1O1O; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1O1P; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1QI8; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1QSH; X-ray; 1.70 A; B/D=1-147.
DR PDB; 1QSI; X-ray; 1.70 A; B/D=1-147.
DR PDB; 1QXD; X-ray; 2.25 A; B/D=1-147.
DR PDB; 1QXE; X-ray; 1.85 A; B/D=1-147.
DR PDB; 1R1X; X-ray; 2.15 A; B=1-147.
DR PDB; 1R1Y; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1RPS; X-ray; 2.11 A; B/D=1-147.
DR PDB; 1RQ3; X-ray; 1.91 A; B/D=1-147.
DR PDB; 1RQ4; X-ray; 2.11 A; B/D=1-147.
DR PDB; 1RQA; X-ray; 2.11 A; B/D=3-147.
DR PDB; 1RVW; X-ray; 2.50 A; B=1-147.
DR PDB; 1SDK; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1SDL; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1THB; X-ray; 1.50 A; B/D=1-147.
DR PDB; 1UIW; X-ray; 1.50 A; B/D/F/H=1-147.
DR PDB; 1VWT; X-ray; 1.90 A; B/D=1-147.
DR PDB; 1XXT; X-ray; 1.91 A; B/D=1-147.
DR PDB; 1XY0; X-ray; 1.99 A; B/D=1-147.
DR PDB; 1XYE; X-ray; 2.13 A; B/D=1-147.
DR PDB; 1XZ2; X-ray; 1.90 A; B/D=1-147.
DR PDB; 1XZ4; X-ray; 2.00 A; B/D=1-147.
DR PDB; 1XZ5; X-ray; 2.11 A; B/D=1-147.
DR PDB; 1XZ7; X-ray; 1.90 A; B/D=1-147.
DR PDB; 1XZU; X-ray; 2.16 A; B/D=1-147.
DR PDB; 1XZV; X-ray; 2.11 A; B/D=1-147.
DR PDB; 1Y09; X-ray; 2.25 A; B/D=1-147.
DR PDB; 1Y0A; X-ray; 2.22 A; B/D=1-147.
DR PDB; 1Y0C; X-ray; 2.30 A; B/D=1-147.
DR PDB; 1Y0D; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1Y0T; X-ray; 2.14 A; B/D=3-147.
DR PDB; 1Y0W; X-ray; 2.14 A; B/D=3-147.
DR PDB; 1Y22; X-ray; 2.16 A; B/D=3-147.
DR PDB; 1Y2Z; X-ray; 2.07 A; B/D=3-147.
DR PDB; 1Y31; X-ray; 2.13 A; B/D=3-147.
DR PDB; 1Y35; X-ray; 2.12 A; B/D=3-147.
DR PDB; 1Y45; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1Y46; X-ray; 2.22 A; B/D=3-147.
DR PDB; 1Y4B; X-ray; 2.10 A; B/D=3-147.
DR PDB; 1Y4F; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1Y4G; X-ray; 1.91 A; B/D=3-147.
DR PDB; 1Y4P; X-ray; 1.98 A; B/D=3-147.
DR PDB; 1Y4Q; X-ray; 2.11 A; B/D=3-147.
DR PDB; 1Y4R; X-ray; 2.22 A; B/D=3-147.
DR PDB; 1Y4V; X-ray; 1.84 A; B/D=3-147.
DR PDB; 1Y5F; X-ray; 2.14 A; B/D=3-147.
DR PDB; 1Y5J; X-ray; 2.03 A; B/D=3-147.
DR PDB; 1Y5K; X-ray; 2.20 A; B/D=3-147.
DR PDB; 1Y7C; X-ray; 2.10 A; B/D=3-147.
DR PDB; 1Y7D; X-ray; 1.90 A; B/D=3-147.
DR PDB; 1Y7G; X-ray; 2.10 A; B/D=3-147.
DR PDB; 1Y7Z; X-ray; 1.98 A; B/D=3-147.
DR PDB; 1Y83; X-ray; 1.90 A; B/D=3-147.
DR PDB; 1Y85; X-ray; 2.13 A; B/D=1-146.
DR PDB; 1Y8W; X-ray; 2.90 A; B/D=1-147.
DR PDB; 1YDZ; X-ray; 3.30 A; B/D=1-147.
DR PDB; 1YE0; X-ray; 2.50 A; B/D=3-147.
DR PDB; 1YE1; X-ray; 4.50 A; B/D=3-147.
DR PDB; 1YE2; X-ray; 1.80 A; B/D=3-147.
DR PDB; 1YEN; X-ray; 2.80 A; B/D=3-147.
DR PDB; 1YEO; X-ray; 2.22 A; B/D=3-147.
DR PDB; 1YEQ; X-ray; 2.75 A; B/D=3-147.
DR PDB; 1YEU; X-ray; 2.12 A; B/D=3-147.
DR PDB; 1YEV; X-ray; 2.11 A; B/D=3-147.
DR PDB; 1YFF; X-ray; 2.40 A; B/D/F/H=1-147.
DR PDB; 1YG5; X-ray; 2.70 A; B/D=3-147.
DR PDB; 1YGD; X-ray; 2.73 A; B/D=3-147.
DR PDB; 1YGF; X-ray; 2.70 A; B/D=3-147.
DR PDB; 1YH9; X-ray; 2.20 A; B/D=1-147.
DR PDB; 1YHE; X-ray; 2.10 A; B/D=1-147.
DR PDB; 1YHR; X-ray; 2.60 A; B/D=1-147.
DR PDB; 1YIE; X-ray; 2.40 A; B/D=3-147.
DR PDB; 1YIH; X-ray; 2.00 A; B/D=3-147.
DR PDB; 1YVQ; X-ray; 1.80 A; B/D=1-147.
DR PDB; 1YVT; X-ray; 1.80 A; B=1-147.
DR PDB; 1YZI; X-ray; 2.07 A; B=1-147.
DR PDB; 2D5Z; X-ray; 1.45 A; B/D=1-147.
DR PDB; 2D60; X-ray; 1.70 A; B/D=1-147.
DR PDB; 2DN1; X-ray; 1.25 A; B=1-147.
DR PDB; 2DN2; X-ray; 1.25 A; B/D=1-147.
DR PDB; 2DN3; X-ray; 1.25 A; B=2-147.
DR PDB; 2DXM; Neutron; 2.10 A; B/D=2-147.
DR PDB; 2H35; NMR; -; B/D=2-147.
DR PDB; 2HBC; X-ray; 2.10 A; B=1-147.
DR PDB; 2HBD; X-ray; 2.20 A; B=1-147.
DR PDB; 2HBE; X-ray; 2.00 A; B=1-147.
DR PDB; 2HBF; X-ray; 2.20 A; B=1-147.
DR PDB; 2HBS; X-ray; 2.05 A; B/D/F/H=1-147.
DR PDB; 2HCO; X-ray; 2.70 A; B=2-147.
DR PDB; 2HHB; X-ray; 1.74 A; B/D=2-147.
DR PDB; 2HHD; X-ray; 2.20 A; B/D=1-147.
DR PDB; 2HHE; X-ray; 2.20 A; B/D=4-147.
DR PDB; 2M6Z; NMR; -; B/D=2-147.
DR PDB; 2W6V; X-ray; 1.80 A; B/D=2-147.
DR PDB; 2W72; X-ray; 1.07 A; B/D=3-147.
DR PDB; 2YRS; X-ray; 2.30 A; B/D/K/O=2-147.
DR PDB; 3B75; X-ray; 2.30 A; B/D/F/H/T=2-147.
DR PDB; 3D17; X-ray; 2.80 A; B/D=2-147.
DR PDB; 3D7O; X-ray; 1.80 A; B=2-147.
DR PDB; 3DUT; X-ray; 1.55 A; B/D=2-147.
DR PDB; 3HHB; X-ray; 1.74 A; B/D=2-147.
DR PDB; 3HXN; X-ray; 2.00 A; B/D=2-147.
DR PDB; 3IC0; X-ray; 1.80 A; B/D=2-146.
DR PDB; 3IC2; X-ray; 2.40 A; B/D=2-147.
DR PDB; 3KMF; Neutron; 2.00 A; C/G=2-147.
DR PDB; 3NL7; X-ray; 1.80 A; B=2-147.
DR PDB; 3NMM; X-ray; 1.60 A; B/D=2-147.
DR PDB; 3ODQ; X-ray; 3.10 A; B/D=2-147.
DR PDB; 3ONZ; X-ray; 2.09 A; B=2-147.
DR PDB; 3OO4; X-ray; 1.90 A; B=2-147.
DR PDB; 3OO5; X-ray; 2.10 A; B=2-147.
DR PDB; 3P5Q; X-ray; 2.00 A; B=2-147.
DR PDB; 3QJB; X-ray; 1.80 A; B=2-147.
DR PDB; 3QJC; X-ray; 2.00 A; B=2-147.
DR PDB; 3QJD; X-ray; 1.56 A; B/D=2-147.
DR PDB; 3QJE; X-ray; 1.80 A; B/D=2-147.
DR PDB; 3R5I; X-ray; 2.20 A; B/D=2-147.
DR PDB; 3S65; X-ray; 1.80 A; B/D=2-147.
DR PDB; 3S66; X-ray; 1.40 A; B=2-147.
DR PDB; 3SZK; X-ray; 3.01 A; B/E=2-147.
DR PDB; 3W4U; X-ray; 1.95 A; B/D/F=2-147.
DR PDB; 3WCP; X-ray; 1.94 A; B/D=2-147.
DR PDB; 4FC3; X-ray; 2.26 A; B=2-147.
DR PDB; 4HHB; X-ray; 1.74 A; B/D=2-147.
DR PDB; 4L7Y; X-ray; 1.80 A; B/D=2-147.
DR PDB; 4MQC; X-ray; 2.20 A; B=2-147.
DR PDB; 4MQG; X-ray; 1.68 A; B=2-147.
DR PDB; 4MQH; X-ray; 2.50 A; B=2-147.
DR PDB; 4MQI; X-ray; 1.92 A; B=2-147.
DR PDB; 6HBW; X-ray; 2.00 A; B/D=2-147.
DR PDBsum; 1A00; -.
DR PDBsum; 1A01; -.
DR PDBsum; 1A0U; -.
DR PDBsum; 1A0Z; -.
DR PDBsum; 1A3N; -.
DR PDBsum; 1A3O; -.
DR PDBsum; 1ABW; -.
DR PDBsum; 1ABY; -.
DR PDBsum; 1AJ9; -.
DR PDBsum; 1B86; -.
DR PDBsum; 1BAB; -.
DR PDBsum; 1BBB; -.
DR PDBsum; 1BIJ; -.
DR PDBsum; 1BUW; -.
DR PDBsum; 1BZ0; -.
DR PDBsum; 1BZ1; -.
DR PDBsum; 1BZZ; -.
DR PDBsum; 1C7B; -.
DR PDBsum; 1C7C; -.
DR PDBsum; 1C7D; -.
DR PDBsum; 1CBL; -.
DR PDBsum; 1CBM; -.
DR PDBsum; 1CH4; -.
DR PDBsum; 1CLS; -.
DR PDBsum; 1CMY; -.
DR PDBsum; 1COH; -.
DR PDBsum; 1DKE; -.
DR PDBsum; 1DXT; -.
DR PDBsum; 1DXU; -.
DR PDBsum; 1DXV; -.
DR PDBsum; 1FN3; -.
DR PDBsum; 1G9V; -.
DR PDBsum; 1GBU; -.
DR PDBsum; 1GBV; -.
DR PDBsum; 1GLI; -.
DR PDBsum; 1GZX; -.
DR PDBsum; 1HAB; -.
DR PDBsum; 1HAC; -.
DR PDBsum; 1HBA; -.
DR PDBsum; 1HBB; -.
DR PDBsum; 1HBS; -.
DR PDBsum; 1HCO; -.
DR PDBsum; 1HDB; -.
DR PDBsum; 1HGA; -.
DR PDBsum; 1HGB; -.
DR PDBsum; 1HGC; -.
DR PDBsum; 1HHO; -.
DR PDBsum; 1IRD; -.
DR PDBsum; 1J3Y; -.
DR PDBsum; 1J3Z; -.
DR PDBsum; 1J40; -.
DR PDBsum; 1J41; -.
DR PDBsum; 1J7S; -.
DR PDBsum; 1J7W; -.
DR PDBsum; 1J7Y; -.
DR PDBsum; 1JY7; -.
DR PDBsum; 1K0Y; -.
DR PDBsum; 1K1K; -.
DR PDBsum; 1KD2; -.
DR PDBsum; 1LFL; -.
DR PDBsum; 1LFQ; -.
DR PDBsum; 1LFT; -.
DR PDBsum; 1LFV; -.
DR PDBsum; 1LFY; -.
DR PDBsum; 1LFZ; -.
DR PDBsum; 1LJW; -.
DR PDBsum; 1M9P; -.
DR PDBsum; 1MKO; -.
DR PDBsum; 1NEJ; -.
DR PDBsum; 1NIH; -.
DR PDBsum; 1NQP; -.
DR PDBsum; 1O1I; -.
DR PDBsum; 1O1J; -.
DR PDBsum; 1O1K; -.
DR PDBsum; 1O1L; -.
DR PDBsum; 1O1M; -.
DR PDBsum; 1O1N; -.
DR PDBsum; 1O1O; -.
DR PDBsum; 1O1P; -.
DR PDBsum; 1QI8; -.
DR PDBsum; 1QSH; -.
DR PDBsum; 1QSI; -.
DR PDBsum; 1QXD; -.
DR PDBsum; 1QXE; -.
DR PDBsum; 1R1X; -.
DR PDBsum; 1R1Y; -.
DR PDBsum; 1RPS; -.
DR PDBsum; 1RQ3; -.
DR PDBsum; 1RQ4; -.
DR PDBsum; 1RQA; -.
DR PDBsum; 1RVW; -.
DR PDBsum; 1SDK; -.
DR PDBsum; 1SDL; -.
DR PDBsum; 1THB; -.
DR PDBsum; 1UIW; -.
DR PDBsum; 1VWT; -.
DR PDBsum; 1XXT; -.
DR PDBsum; 1XY0; -.
DR PDBsum; 1XYE; -.
DR PDBsum; 1XZ2; -.
DR PDBsum; 1XZ4; -.
DR PDBsum; 1XZ5; -.
DR PDBsum; 1XZ7; -.
DR PDBsum; 1XZU; -.
DR PDBsum; 1XZV; -.
DR PDBsum; 1Y09; -.
DR PDBsum; 1Y0A; -.
DR PDBsum; 1Y0C; -.
DR PDBsum; 1Y0D; -.
DR PDBsum; 1Y0T; -.
DR PDBsum; 1Y0W; -.
DR PDBsum; 1Y22; -.
DR PDBsum; 1Y2Z; -.
DR PDBsum; 1Y31; -.
DR PDBsum; 1Y35; -.
DR PDBsum; 1Y45; -.
DR PDBsum; 1Y46; -.
DR PDBsum; 1Y4B; -.
DR PDBsum; 1Y4F; -.
DR PDBsum; 1Y4G; -.
DR PDBsum; 1Y4P; -.
DR PDBsum; 1Y4Q; -.
DR PDBsum; 1Y4R; -.
DR PDBsum; 1Y4V; -.
DR PDBsum; 1Y5F; -.
DR PDBsum; 1Y5J; -.
DR PDBsum; 1Y5K; -.
DR PDBsum; 1Y7C; -.
DR PDBsum; 1Y7D; -.
DR PDBsum; 1Y7G; -.
DR PDBsum; 1Y7Z; -.
DR PDBsum; 1Y83; -.
DR PDBsum; 1Y85; -.
DR PDBsum; 1Y8W; -.
DR PDBsum; 1YDZ; -.
DR PDBsum; 1YE0; -.
DR PDBsum; 1YE1; -.
DR PDBsum; 1YE2; -.
DR PDBsum; 1YEN; -.
DR PDBsum; 1YEO; -.
DR PDBsum; 1YEQ; -.
DR PDBsum; 1YEU; -.
DR PDBsum; 1YEV; -.
DR PDBsum; 1YFF; -.
DR PDBsum; 1YG5; -.
DR PDBsum; 1YGD; -.
DR PDBsum; 1YGF; -.
DR PDBsum; 1YH9; -.
DR PDBsum; 1YHE; -.
DR PDBsum; 1YHR; -.
DR PDBsum; 1YIE; -.
DR PDBsum; 1YIH; -.
DR PDBsum; 1YVQ; -.
DR PDBsum; 1YVT; -.
DR PDBsum; 1YZI; -.
DR PDBsum; 2D5Z; -.
DR PDBsum; 2D60; -.
DR PDBsum; 2DN1; -.
DR PDBsum; 2DN2; -.
DR PDBsum; 2DN3; -.
DR PDBsum; 2DXM; -.
DR PDBsum; 2H35; -.
DR PDBsum; 2HBC; -.
DR PDBsum; 2HBD; -.
DR PDBsum; 2HBE; -.
DR PDBsum; 2HBF; -.
DR PDBsum; 2HBS; -.
DR PDBsum; 2HCO; -.
DR PDBsum; 2HHB; -.
DR PDBsum; 2HHD; -.
DR PDBsum; 2HHE; -.
DR PDBsum; 2M6Z; -.
DR PDBsum; 2W6V; -.
DR PDBsum; 2W72; -.
DR PDBsum; 2YRS; -.
DR PDBsum; 3B75; -.
DR PDBsum; 3D17; -.
DR PDBsum; 3D7O; -.
DR PDBsum; 3DUT; -.
DR PDBsum; 3HHB; -.
DR PDBsum; 3HXN; -.
DR PDBsum; 3IC0; -.
DR PDBsum; 3IC2; -.
DR PDBsum; 3KMF; -.
DR PDBsum; 3NL7; -.
DR PDBsum; 3NMM; -.
DR PDBsum; 3ODQ; -.
DR PDBsum; 3ONZ; -.
DR PDBsum; 3OO4; -.
DR PDBsum; 3OO5; -.
DR PDBsum; 3P5Q; -.
DR PDBsum; 3QJB; -.
DR PDBsum; 3QJC; -.
DR PDBsum; 3QJD; -.
DR PDBsum; 3QJE; -.
DR PDBsum; 3R5I; -.
DR PDBsum; 3S65; -.
DR PDBsum; 3S66; -.
DR PDBsum; 3SZK; -.
DR PDBsum; 3W4U; -.
DR PDBsum; 3WCP; -.
DR PDBsum; 4FC3; -.
DR PDBsum; 4HHB; -.
DR PDBsum; 4L7Y; -.
DR PDBsum; 4MQC; -.
DR PDBsum; 4MQG; -.
DR PDBsum; 4MQH; -.
DR PDBsum; 4MQI; -.
DR PDBsum; 6HBW; -.
DR ProteinModelPortal; P68871; -.
DR SMR; P68871; 2-147.
DR IntAct; P68871; 6.
DR MINT; MINT-5000306; -.
DR ChEMBL; CHEMBL4331; -.
DR DrugBank; DB00893; Iron Dextran.
DR PhosphoSite; P68871; -.
DR DMDM; 56749856; -.
DR REPRODUCTION-2DPAGE; IPI00654755; -.
DR REPRODUCTION-2DPAGE; P68871; -.
DR SWISS-2DPAGE; P68871; -.
DR UCD-2DPAGE; P02023; -.
DR UCD-2DPAGE; P68871; -.
DR PaxDb; P68871; -.
DR PeptideAtlas; P68871; -.
DR PRIDE; P68871; -.
DR DNASU; 3043; -.
DR Ensembl; ENST00000335295; ENSP00000333994; ENSG00000244734.
DR GeneID; 3043; -.
DR KEGG; hsa:3043; -.
DR UCSC; uc001mae.1; human.
DR CTD; 3043; -.
DR GeneCards; GC11M005257; -.
DR HGNC; HGNC:4827; HBB.
DR HPA; CAB009526; -.
DR HPA; HPA043234; -.
DR MIM; 140700; phenotype.
DR MIM; 141900; gene+phenotype.
DR MIM; 603902; phenotype.
DR MIM; 603903; phenotype.
DR MIM; 613985; phenotype.
DR neXtProt; NX_P68871; -.
DR Orphanet; 330041; Autosomal dominant methemoglobinemia.
DR Orphanet; 231222; Beta-thalassemia intermedia.
DR Orphanet; 231214; Beta-thalassemia major.
DR Orphanet; 231237; Delta-beta thalassemia.
DR Orphanet; 231226; Dominant beta-thalassemia.
DR Orphanet; 178330; Heinz body anemia.
DR Orphanet; 231242; Hemoglobin C - beta-thalassemia.
DR Orphanet; 2132; Hemoglobin C disease.
DR Orphanet; 90039; Hemoglobin D disease.
DR Orphanet; 231249; Hemoglobin E - beta-thalassemia.
DR Orphanet; 2133; Hemoglobin E disease.
DR Orphanet; 330032; Hemoglobin Lepore - beta-thalassemia.
DR Orphanet; 46532; Hereditary persistence of fetal hemoglobin - beta-thalassemia.
DR Orphanet; 251380; Hereditary persistence of fetal hemoglobin - sickle cell disease.
DR Orphanet; 251359; Sickle cell - beta-thalassemia disease.
DR Orphanet; 251365; Sickle cell - hemoglobin C disease.
DR Orphanet; 251370; Sickle cell - hemoglobin D disease.
DR Orphanet; 251375; Sickle cell - hemoglobin E disease.
DR Orphanet; 232; Sickle cell anemia.
DR PharmGKB; PA29202; -.
DR eggNOG; NOG269316; -.
DR HOVERGEN; HBG009709; -.
DR InParanoid; P68871; -.
DR KO; K13823; -.
DR OMA; DAVMNNP; -.
DR OrthoDB; EOG7B8S5H; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; HBB; human.
DR EvolutionaryTrace; P68871; -.
DR GeneWiki; HBB; -.
DR GenomeRNAi; 3043; -.
DR NextBio; 12048; -.
DR PMAP-CutDB; P68871; -.
DR PRO; PR:P68871; -.
DR ArrayExpress; P68871; -.
DR Bgee; P68871; -.
DR Genevestigator; P68871; -.
DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0031838; C:haptoglobin-hemoglobin complex; IDA:BHF-UCL.
DR GO; GO:0005833; C:hemoglobin complex; NAS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0030492; F:hemoglobin binding; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0019825; F:oxygen binding; IDA:UniProtKB.
DR GO; GO:0005344; F:oxygen transporter activity; NAS:UniProtKB.
DR GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0042744; P:hydrogen peroxide catabolic process; IDA:BHF-UCL.
DR GO; GO:0030185; P:nitric oxide transport; NAS:UniProtKB.
DR GO; GO:0010942; P:positive regulation of cell death; IDA:BHF-UCL.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; NAS:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IDA:BHF-UCL.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:UniProtKB-KW.
DR GO; GO:0050880; P:regulation of blood vessel size; IEA:UniProtKB-KW.
DR GO; GO:0070293; P:renal absorption; IMP:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.10.490.10; -; 1.
DR InterPro; IPR000971; Globin.
DR InterPro; IPR009050; Globin-like.
DR InterPro; IPR012292; Globin_dom.
DR InterPro; IPR002337; Haemoglobin_b.
DR Pfam; PF00042; Globin; 1.
DR PRINTS; PR00814; BETAHAEM.
DR SUPFAM; SSF46458; SSF46458; 1.
DR PROSITE; PS01033; GLOBIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Congenital dyserythropoietic anemia; Direct protein sequencing;
KW Disease mutation; Glycation; Glycoprotein; Heme;
KW Hereditary hemolytic anemia; Hypotensive agent; Iron; Metal-binding;
KW Oxygen transport; Polymorphism; Pyruvate; Reference proteome;
KW S-nitrosylation; Transport; Vasoactive.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 147 Hemoglobin subunit beta.
FT /FTId=PRO_0000052976.
FT PEPTIDE 33 42 LVV-hemorphin-7.
FT /FTId=PRO_0000296641.
FT PEPTIDE 33 39 Spinorphin.
FT /FTId=PRO_0000424226.
FT METAL 64 64 Iron (heme distal ligand).
FT METAL 93 93 Iron (heme proximal ligand).
FT BINDING 2 2 2,3-bisphosphoglycerate; via amino
FT nitrogen.
FT BINDING 3 3 2,3-bisphosphoglycerate.
FT BINDING 83 83 2,3-bisphosphoglycerate.
FT BINDING 144 144 2,3-bisphosphoglycerate.
FT SITE 60 60 Not glycated.
FT SITE 83 83 Not glycated.
FT SITE 96 96 Not glycated.
FT SITE 142 142 Susceptible to oxidation; associated with
FT variant Atlanta, variant non-spherocytic
FT haemolytic anemia and variant
FT Christchurch.
FT SITE 145 145 Aspirin-acetylated lysine.
FT MOD_RES 2 2 N-acetylalanine; in variant Raleigh.
FT MOD_RES 2 2 N-acetylvaline (By similarity).
FT MOD_RES 2 2 N-pyruvate 2-iminyl-valine; in Hb A1b.
FT MOD_RES 94 94 S-nitrosocysteine.
FT CARBOHYD 2 2 N-linked (Glc) (glycation); in Hb A1c.
FT CARBOHYD 9 9 N-linked (Glc) (glycation).
FT CARBOHYD 18 18 N-linked (Glc) (glycation).
FT CARBOHYD 67 67 N-linked (Glc) (glycation).
FT CARBOHYD 121 121 N-linked (Glc) (glycation).
FT CARBOHYD 145 145 N-linked (Glc) (glycation).
FT VARIANT 2 2 V -> A (in Raleigh; O(2) affinity down;
FT dbSNP:rs33949930).
FT /FTId=VAR_002856.
FT VARIANT 3 3 H -> L (in Graz; dbSNP:rs35906307).
FT /FTId=VAR_002857.
FT VARIANT 3 3 H -> Q (in Okayama; O(2) affinity up;
FT dbSNP:rs713040).
FT /FTId=VAR_002858.
FT VARIANT 3 3 H -> R (in Deer Lodge; O(2) affinity up;
FT dbSNP:rs33983205).
FT /FTId=VAR_002859.
FT VARIANT 3 3 H -> Y (in Fukuoka; dbSNP:rs35906307).
FT /FTId=VAR_002860.
FT VARIANT 6 6 P -> R (in Warwickshire;
FT dbSNP:rs34769005).
FT /FTId=VAR_002861.
FT VARIANT 7 7 E -> A (in G-Makassar; dbSNP:rs334).
FT /FTId=VAR_002862.
FT VARIANT 7 7 E -> K (in C; dbSNP:rs33930165).
FT /FTId=VAR_002864.
FT VARIANT 7 7 E -> Q (in Machida; dbSNP:rs33930165).
FT /FTId=VAR_002865.
FT VARIANT 7 7 E -> V (in S; sickle cell anemia;
FT dbSNP:rs334).
FT /FTId=VAR_002863.
FT VARIANT 8 8 E -> G (in G-San Jose; mildly unstable;
FT dbSNP:rs34948328).
FT /FTId=VAR_002866.
FT VARIANT 8 8 E -> K (in G-Siriraj; dbSNP:rs34948328).
FT /FTId=VAR_002867.
FT VARIANT 9 9 K -> E (in N-Timone; dbSNP:rs33932981).
FT /FTId=VAR_002868.
FT VARIANT 9 9 K -> Q (in J-Luhe; dbSNP:rs33926764).
FT /FTId=VAR_002869.
FT VARIANT 9 9 K -> T (in Rio Grande).
FT /FTId=VAR_002870.
FT VARIANT 10 10 S -> C (in Porto Alegre; O(2) affinity
FT up; dbSNP:rs33918131).
FT /FTId=VAR_002871.
FT VARIANT 11 11 A -> D (in Ankara; dbSNP:rs33947457).
FT /FTId=VAR_002872.
FT VARIANT 11 11 A -> V (in Iraq-Halabja).
FT /FTId=VAR_025393.
FT VARIANT 12 12 V -> D (in Windsor; O(2) affinity up;
FT unstable; dbSNP:rs33974228).
FT /FTId=VAR_002873.
FT VARIANT 12 12 V -> I (in Hamilton).
FT /FTId=VAR_002874.
FT VARIANT 14 14 A -> D (in J-Lens; dbSNP:rs35203747).
FT /FTId=VAR_002875.
FT VARIANT 15 15 L -> P (in Saki; unstable).
FT /FTId=VAR_002876.
FT VARIANT 15 15 L -> R (in Soegn; unstable;
FT dbSNP:rs33935445).
FT /FTId=VAR_002877.
FT VARIANT 16 16 W -> G (in Randwick; unstable;
FT dbSNP:rs33946157).
FT /FTId=VAR_002878.
FT VARIANT 16 16 W -> R (in Belfast; O(2) affinity up;
FT unstable; dbSNP:rs33946157).
FT /FTId=VAR_002879.
FT VARIANT 17 17 G -> D (in J-Baltimore/J-Trinidad/J-
FT Ireland/J-Georgia/N-New Haven).
FT /FTId=VAR_002880.
FT VARIANT 17 17 G -> R (in D-Bushman).
FT /FTId=VAR_002881.
FT VARIANT 18 18 K -> E (in Nagasaki; dbSNP:rs33986703).
FT /FTId=VAR_002882.
FT VARIANT 18 18 K -> N (in J-Amiens; dbSNP:rs36006214).
FT /FTId=VAR_002883.
FT VARIANT 18 18 K -> Q (in Nikosia; dbSNP:rs33986703).
FT /FTId=VAR_002884.
FT VARIANT 19 19 V -> M (in Baden; slightly unstable;
FT dbSNP:rs35802118).
FT /FTId=VAR_002885.
FT VARIANT 20 20 N -> D (in Alamo; dbSNP:rs34866629).
FT /FTId=VAR_002886.
FT VARIANT 20 20 N -> K (in D-Ouleh RABAH).
FT /FTId=VAR_002887.
FT VARIANT 20 20 N -> S (in Malay; dbSNP:rs33972047).
FT /FTId=VAR_002888.
FT VARIANT 21 21 V -> M (in Olympia; O(2) affinity up;
FT dbSNP:rs35890959).
FT /FTId=VAR_002889.
FT VARIANT 22 22 D -> G (in Connecticut; O(2) affinity
FT down; dbSNP:rs33977536).
FT /FTId=VAR_002890.
FT VARIANT 22 22 D -> H (in Karlskoga; dbSNP:rs33950093).
FT /FTId=VAR_002892.
FT VARIANT 22 22 D -> N (in Cocody).
FT /FTId=VAR_002891.
FT VARIANT 22 22 D -> Y (in Yusa).
FT /FTId=VAR_002893.
FT VARIANT 23 23 E -> A (in G-Coushatta/G-Saskatoon/G-
FT Taegu/Hsin Chu; dbSNP:rs33936254).
FT /FTId=VAR_002894.
FT VARIANT 23 23 E -> G (in G-Taipei).
FT /FTId=VAR_002895.
FT VARIANT 23 23 E -> K (in E-Saskatoon; unstable).
FT /FTId=VAR_002896.
FT VARIANT 23 23 E -> Q (in D-Iran).
FT /FTId=VAR_002897.
FT VARIANT 23 23 E -> V (in D-Granada).
FT /FTId=VAR_002898.
FT VARIANT 24 24 V -> D (in Strasbourg; O(2) affinity up).
FT /FTId=VAR_002899.
FT VARIANT 24 24 V -> F (in Palmerston North; O(2)
FT affinity up; unstable).
FT /FTId=VAR_002900.
FT VARIANT 24 24 V -> G (in Miyashiro; O(2) affinity up;
FT unstable).
FT /FTId=VAR_002901.
FT VARIANT 24 24 Missing (in Freiburg; dbSNP:rs34160180).
FT /FTId=VAR_069169.
FT VARIANT 25 25 G -> D (in Moscva; O(2) affinity down;
FT unstable).
FT /FTId=VAR_002902.
FT VARIANT 25 25 G -> R (in Riverdale-Bronx; O(2) affinity
FT up; unstable).
FT /FTId=VAR_002903.
FT VARIANT 25 25 G -> V (in Savannah; unstable).
FT /FTId=VAR_002904.
FT VARIANT 26 26 G -> D (in J-Auckland; unstable; O(2)
FT affinity down).
FT /FTId=VAR_002905.
FT VARIANT 26 26 G -> R (in G-Taiwan Ami).
FT /FTId=VAR_002906.
FT VARIANT 27 27 E -> K (in E).
FT /FTId=VAR_002907.
FT VARIANT 27 27 E -> V (in Henri Mondor; slightly
FT unstable).
FT /FTId=VAR_002908.
FT VARIANT 28 28 A -> D (in Volga/Drenthe; unstable).
FT /FTId=VAR_002909.
FT VARIANT 28 28 A -> S (in Knossos).
FT /FTId=VAR_002910.
FT VARIANT 28 28 A -> V (in Grange-blanche; O(2) affinity
FT up).
FT /FTId=VAR_002911.
FT VARIANT 29 29 L -> P (in Genova/Hyogo; unstable).
FT /FTId=VAR_002912.
FT VARIANT 29 29 L -> Q (in St Louis).
FT /FTId=VAR_035236.
FT VARIANT 30 30 G -> D (in Lufkin; unstable).
FT /FTId=VAR_002913.
FT VARIANT 31 31 R -> S (in Tacoma; unstable;
FT dbSNP:rs1135071).
FT /FTId=VAR_002914.
FT VARIANT 32 32 L -> P (in Yokohama; unstable).
FT /FTId=VAR_002915.
FT VARIANT 33 33 L -> R (in Castilla; unstable).
FT /FTId=VAR_002916.
FT VARIANT 33 33 L -> V (in Muscat; slightly unstable).
FT /FTId=VAR_002917.
FT VARIANT 35 35 V -> D (in Santander; unstable).
FT /FTId=VAR_025394.
FT VARIANT 35 35 V -> F (in Pitie-Salpetriere; O(2)
FT affinity up).
FT /FTId=VAR_002918.
FT VARIANT 35 35 V -> L (in Nantes; increased oxygen
FT affinity).
FT /FTId=VAR_025395.
FT VARIANT 36 36 Y -> F (in Philly; O(2) affinity up;
FT unstable).
FT /FTId=VAR_002919.
FT VARIANT 37 37 P -> R (in Sunnybrook).
FT /FTId=VAR_002920.
FT VARIANT 37 37 P -> S (in North Chicago; O(2) affinity
FT up).
FT /FTId=VAR_002921.
FT VARIANT 37 37 P -> T (in Linkoping/Finlandia; O(2)
FT affinity up).
FT /FTId=VAR_002922.
FT VARIANT 38 38 W -> G (in Howick).
FT /FTId=VAR_002923.
FT VARIANT 38 38 W -> R (in Rothschild; O(2) affinity
FT down).
FT /FTId=VAR_002925.
FT VARIANT 38 38 W -> S (in Hirose; O(2) affinity up).
FT /FTId=VAR_002924.
FT VARIANT 39 39 T -> N (in Hinwil; O(2) affinity up).
FT /FTId=VAR_002926.
FT VARIANT 40 40 Q -> E (in Vaasa; unstable;
FT dbSNP:rs76728603).
FT /FTId=VAR_002927.
FT VARIANT 40 40 Q -> K (in Alabama; dbSNP:rs76728603).
FT /FTId=VAR_002928.
FT VARIANT 40 40 Q -> R (in Tianshui).
FT /FTId=VAR_002929.
FT VARIANT 42 42 F -> Y (in Mequon).
FT /FTId=VAR_002930.
FT VARIANT 42 42 Missing (in Bruxelles).
FT /FTId=VAR_035237.
FT VARIANT 43 43 F -> L (in Louisville; unstable).
FT /FTId=VAR_002931.
FT VARIANT 43 43 F -> S (in Hammersmith).
FT /FTId=VAR_035239.
FT VARIANT 43 43 Missing (in Bruxelles).
FT /FTId=VAR_035238.
FT VARIANT 44 44 E -> Q (in Hoshida/Chaya).
FT /FTId=VAR_002932.
FT VARIANT 45 45 S -> C (in Mississippi).
FT /FTId=VAR_002933.
FT VARIANT 46 46 F -> S (in Cheverly; unstable).
FT /FTId=VAR_002934.
FT VARIANT 47 47 G -> E (in K-Ibadan).
FT /FTId=VAR_002935.
FT VARIANT 48 48 D -> A (in Avicenna).
FT /FTId=VAR_002936.
FT VARIANT 48 48 D -> G (in Gavello).
FT /FTId=VAR_002937.
FT VARIANT 48 48 D -> Y (in Maputo).
FT /FTId=VAR_002938.
FT VARIANT 49 49 L -> P (in Bab-Saadoum; slightly
FT unstable).
FT /FTId=VAR_002939.
FT VARIANT 50 50 S -> F (in Las Palmas; slightly
FT unstable).
FT /FTId=VAR_002940.
FT VARIANT 51 51 T -> K (in Edmonton).
FT /FTId=VAR_002941.
FT VARIANT 52 52 P -> R (in Willamette; O(2) affinity up;
FT unstable).
FT /FTId=VAR_002942.
FT VARIANT 53 53 D -> A (in Ocho Rios).
FT /FTId=VAR_002943.
FT VARIANT 53 53 D -> H (in Summer Hill).
FT /FTId=VAR_002944.
FT VARIANT 55 55 V -> D (in Jacksonville; O(2) affinity
FT up; unstable).
FT /FTId=VAR_002945.
FT VARIANT 56 56 M -> K (in Matera; unstable).
FT /FTId=VAR_002946.
FT VARIANT 57 57 G -> R (in Hamadan).
FT /FTId=VAR_002947.
FT VARIANT 58 58 N -> K (in G-ferrara; unstable).
FT /FTId=VAR_002948.
FT VARIANT 59 59 P -> R (in Dhofar/Yukuhashi).
FT /FTId=VAR_002949.
FT VARIANT 60 60 K -> E (in I-High Wycombe).
FT /FTId=VAR_002950.
FT VARIANT 61 61 V -> A (in Collingwood; unstable).
FT /FTId=VAR_002951.
FT VARIANT 62 62 K -> E (in N-Seatlle).
FT /FTId=VAR_002952.
FT VARIANT 62 62 K -> M (in Bologna; O(2) affinity down).
FT /FTId=VAR_002953.
FT VARIANT 62 62 K -> N (in Hikari).
FT /FTId=VAR_002954.
FT VARIANT 63 63 A -> D (in J-Europa).
FT /FTId=VAR_002955.
FT VARIANT 63 63 A -> P (in Duarte; unstable).
FT /FTId=VAR_002956.
FT VARIANT 64 64 H -> Y (in M-Saskatoon; O(2) affinity
FT up).
FT /FTId=VAR_002957.
FT VARIANT 66 66 K -> M (in J-Antakya).
FT /FTId=VAR_002958.
FT VARIANT 66 66 K -> N (in J-Sicilia).
FT /FTId=VAR_002959.
FT VARIANT 66 66 K -> Q (in J-Cairo).
FT /FTId=VAR_002960.
FT VARIANT 67 67 K -> T (in Chico; O(2) affinity down).
FT /FTId=VAR_002961.
FT VARIANT 68 68 V -> A (in Sydney; unstable).
FT /FTId=VAR_002962.
FT VARIANT 68 68 V -> D (in Bristol).
FT /FTId=VAR_035240.
FT VARIANT 68 68 V -> G (in non-spherocytic haemolytic
FT anemia; Manukau; dbSNP:rs33918343).
FT /FTId=VAR_040060.
FT VARIANT 68 68 V -> M (in Alesha; unstable).
FT /FTId=VAR_002963.
FT VARIANT 69 69 L -> H (in Brisbane; O(2) affinity up).
FT /FTId=VAR_002964.
FT VARIANT 69 69 L -> P (in Mizuho; unstable).
FT /FTId=VAR_002965.
FT VARIANT 70 70 G -> D (in Rambam).
FT /FTId=VAR_002966.
FT VARIANT 70 70 G -> R (in Kenitra).
FT /FTId=VAR_002967.
FT VARIANT 70 70 G -> S (in City of Hope).
FT /FTId=VAR_002968.
FT VARIANT 71 71 A -> D (in Seattle; O(2) affinity down;
FT unstable).
FT /FTId=VAR_002969.
FT VARIANT 72 72 F -> S (in Christchurch; unstable).
FT /FTId=VAR_002970.
FT VARIANT 74 74 D -> G (in Tilburg; O(2) affinity down).
FT /FTId=VAR_002971.
FT VARIANT 74 74 D -> V (in Mobile; O(2) affinity down).
FT /FTId=VAR_002972.
FT VARIANT 74 74 D -> Y (in Vancouver; O(2) affinity
FT down).
FT /FTId=VAR_002973.
FT VARIANT 75 75 G -> R (in Aalborg; unstable).
FT /FTId=VAR_002974.
FT VARIANT 75 75 G -> V (in Bushwick; unstable).
FT /FTId=VAR_002975.
FT VARIANT 76 76 L -> P (in Atlanta; unstable).
FT /FTId=VAR_002976.
FT VARIANT 76 76 L -> R (in Pasadena; O(2) affinity up;
FT unstable).
FT /FTId=VAR_002977.
FT VARIANT 77 77 A -> D (in J-Chicago).
FT /FTId=VAR_002978.
FT VARIANT 78 78 H -> D (in J-Iran).
FT /FTId=VAR_002979.
FT VARIANT 78 78 H -> R (in Costa Rica).
FT /FTId=VAR_002980.
FT VARIANT 78 78 H -> Y (in Fukuyama).
FT /FTId=VAR_002981.
FT VARIANT 79 79 L -> R (in Quin-hai).
FT /FTId=VAR_002982.
FT VARIANT 80 80 D -> Y (in Tampa).
FT /FTId=VAR_002983.
FT VARIANT 81 81 N -> K (in G-Szuhu/Gifu).
FT /FTId=VAR_002984.
FT VARIANT 82 82 L -> H (in La Roche-sur-Yon; unstable and
FT O(2) affinity up).
FT /FTId=VAR_012663.
FT VARIANT 82 82 L -> R (in Baylor; unstable).
FT /FTId=VAR_002985.
FT VARIANT 82 82 L -> V (in dbSNP:rs11549406).
FT /FTId=VAR_049273.
FT VARIANT 83 83 K -> M (in Helsinki; O(2) affinity up).
FT /FTId=VAR_002986.
FT VARIANT 83 83 K -> N (in Providence).
FT /FTId=VAR_012664.
FT VARIANT 84 84 G -> D (in Pyrgos).
FT /FTId=VAR_025396.
FT VARIANT 84 84 G -> R (in Muskegon).
FT /FTId=VAR_002987.
FT VARIANT 85 85 T -> I (in Kofu).
FT /FTId=VAR_002988.
FT VARIANT 87 87 A -> D (in Olomouc; O(2) affinity up).
FT /FTId=VAR_002989.
FT VARIANT 88 88 T -> I (in Quebec-Chori).
FT /FTId=VAR_002990.
FT VARIANT 88 88 T -> K (in D-Ibadan).
FT /FTId=VAR_002991.
FT VARIANT 88 88 T -> P (in Valletta).
FT /FTId=VAR_002992.
FT VARIANT 89 89 L -> P (in Santa Ana; unstable).
FT /FTId=VAR_002993.
FT VARIANT 89 89 L -> R (in Boras; unstable).
FT /FTId=VAR_002994.
FT VARIANT 90 90 S -> N (in Creteil; O(2) affinity up).
FT /FTId=VAR_002995.
FT VARIANT 90 90 S -> R (in Vanderbilt; O(2) affinity up).
FT /FTId=VAR_002996.
FT VARIANT 91 91 E -> D (in Pierre-Benite; O(2) affinity
FT up).
FT /FTId=VAR_002997.
FT VARIANT 91 91 E -> K (in Agenogi; O(2) affinity down).
FT /FTId=VAR_002998.
FT VARIANT 92 92 L -> P (in Sabine; unstable).
FT /FTId=VAR_002999.
FT VARIANT 92 92 L -> R (in Caribbean; O(2) affinity down;
FT unstable).
FT /FTId=VAR_003000.
FT VARIANT 93 93 H -> D (in J-Altgelds Gardens; unstable).
FT /FTId=VAR_003001.
FT VARIANT 93 93 H -> N (in Isehara; unstable).
FT /FTId=VAR_003002.
FT VARIANT 93 93 H -> P (in Newcastle and Duino;
FT associated with S-104 in Duino;
FT unstable).
FT /FTId=VAR_003003.
FT VARIANT 93 93 H -> Q (in Istambul; O(2) affinity up;
FT unstable).
FT /FTId=VAR_003004.
FT VARIANT 94 94 C -> R (in Okazaki; O(2) affinity up;
FT unstable).
FT /FTId=VAR_003005.
FT VARIANT 95 95 D -> G (in Chandigarh).
FT /FTId=VAR_003006.
FT VARIANT 95 95 D -> H (in Barcelona; O(2) affinity up).
FT /FTId=VAR_003007.
FT VARIANT 95 95 D -> N (in Bunbury; O(2) affinity up).
FT /FTId=VAR_003008.
FT VARIANT 96 96 K -> M (in J-Cordoba).
FT /FTId=VAR_003009.
FT VARIANT 96 96 K -> N (in Detroit).
FT /FTId=VAR_003010.
FT VARIANT 97 97 L -> P (in Debrousse; unstable; O(2)
FT affinity up).
FT /FTId=VAR_003011.
FT VARIANT 97 97 L -> V (in Regina; O(2) affinity up).
FT /FTId=VAR_003012.
FT VARIANT 98 98 H -> L (in Wood; O(2) affinity up).
FT /FTId=VAR_003013.
FT VARIANT 98 98 H -> P (in Nagoya; O(2) affinity up;
FT unstable).
FT /FTId=VAR_003014.
FT VARIANT 98 98 H -> Q (in Malmoe; O(2) affinity up).
FT /FTId=VAR_003015.
FT VARIANT 98 98 H -> Y (in Moriguchi).
FT /FTId=VAR_003016.
FT VARIANT 99 99 V -> G (in Nottingham; unstable).
FT /FTId=VAR_003017.
FT VARIANT 100 100 D -> E (in Coimbra; O(2) affinity up).
FT /FTId=VAR_003018.
FT VARIANT 101 101 P -> L (in Brigham; O(2) affinity up).
FT /FTId=VAR_003019.
FT VARIANT 101 101 P -> R (in New Mexico).
FT /FTId=VAR_003020.
FT VARIANT 102 102 E -> D (in Potomac; O(2) affinity up).
FT /FTId=VAR_003021.
FT VARIANT 102 102 E -> G (in Alberta; O(2) affinity up).
FT /FTId=VAR_003022.
FT VARIANT 102 102 E -> K (in British Columbia; O(2)
FT affinity up).
FT /FTId=VAR_003023.
FT VARIANT 102 102 E -> Q (in Rush; unstable).
FT /FTId=VAR_003024.
FT VARIANT 103 103 N -> S (in Beth Israel; O(2) affinity
FT down; unstable).
FT /FTId=VAR_003025.
FT VARIANT 103 103 N -> Y (in St Mande; O(2) affinity down).
FT /FTId=VAR_003026.
FT VARIANT 104 104 F -> L (in Heathrow; O(2) affinity up).
FT /FTId=VAR_003027.
FT VARIANT 105 105 R -> S (in Camperdown and Duino;
FT associated with P-92 in Duino; unstable).
FT /FTId=VAR_003028.
FT VARIANT 105 105 R -> T (in Sherwood Forest).
FT /FTId=VAR_003029.
FT VARIANT 108 108 G -> R (in Burke; O(2) affinity down;
FT unstable).
FT /FTId=VAR_003030.
FT VARIANT 109 109 N -> K (in Presbyterian; O(2) affinity
FT down; unstable).
FT /FTId=VAR_003031.
FT VARIANT 110 110 V -> M (in San Diego; O(2) affinity up).
FT /FTId=VAR_003032.
FT VARIANT 111 111 L -> P (in Showa-Yakushiji).
FT /FTId=VAR_003033.
FT VARIANT 112 112 V -> A (in Stanmore; O(2) affinity down;
FT unstable).
FT /FTId=VAR_003034.
FT VARIANT 113 113 C -> F (in Canterbury).
FT /FTId=VAR_025397.
FT VARIANT 113 113 C -> R (in Indianapolis).
FT /FTId=VAR_003035.
FT VARIANT 113 113 C -> Y (in Yahata).
FT /FTId=VAR_003036.
FT VARIANT 115 115 L -> M (in Zengcheng).
FT /FTId=VAR_010144.
FT VARIANT 115 115 L -> P (in Durham-N.C./Brescia; causes
FT beta-thalassemia).
FT /FTId=VAR_010145.
FT VARIANT 116 116 A -> D (in Hradec Kralove; unstable;
FT causes severe beta-thalassemia).
FT /FTId=VAR_003037.
FT VARIANT 116 116 A -> P (in Madrid; unstable).
FT /FTId=VAR_003038.
FT VARIANT 117 117 H -> L (in Vexin; increased oxygen
FT affinity).
FT /FTId=VAR_025398.
FT VARIANT 117 117 H -> Q (in Hafnia).
FT /FTId=VAR_003039.
FT VARIANT 118 118 H -> P (in Saitama; unstable).
FT /FTId=VAR_003040.
FT VARIANT 118 118 H -> R (in P-Galveston).
FT /FTId=VAR_003041.
FT VARIANT 118 118 H -> Y (in Tsukumi).
FT /FTId=VAR_025399.
FT VARIANT 120 120 G -> A (in Iowa).
FT /FTId=VAR_003042.
FT VARIANT 121 121 K -> E (in Hijiyama).
FT /FTId=VAR_003043.
FT VARIANT 121 121 K -> I (in Jianghua).
FT /FTId=VAR_003044.
FT VARIANT 121 121 K -> Q (in Takamatsu).
FT /FTId=VAR_003045.
FT VARIANT 122 122 E -> A (in D-Neath).
FT /FTId=VAR_003046.
FT VARIANT 122 122 E -> G (in St Francis).
FT /FTId=VAR_003047.
FT VARIANT 122 122 E -> K (in O-Arab).
FT /FTId=VAR_003049.
FT VARIANT 122 122 E -> Q (in D-Los Angeles/D-Punjab/D-
FT Portugal/D-Chicago/D-Oak Ridge).
FT /FTId=VAR_003048.
FT VARIANT 122 122 E -> V (in D-Camperdown/Beograd).
FT /FTId=VAR_003050.
FT VARIANT 124 124 T -> I (in Villejuif; asymptomatic
FT variant).
FT /FTId=VAR_003051.
FT VARIANT 125 125 P -> Q (in Ty Gard; O(2) affinity up).
FT /FTId=VAR_003053.
FT VARIANT 125 125 P -> R (in Khartoum; unstable).
FT /FTId=VAR_003052.
FT VARIANT 125 125 P -> S (in Tunis).
FT /FTId=VAR_003054.
FT VARIANT 127 127 V -> A (in Beirut).
FT /FTId=VAR_003055.
FT VARIANT 127 127 V -> E (in Hofu; unstable).
FT /FTId=VAR_003057.
FT VARIANT 127 127 V -> G (in Dhonburi/Neapolis; unstable;
FT beta-thalassemia).
FT /FTId=VAR_003056.
FT VARIANT 128 128 Q -> E (in Complutense).
FT /FTId=VAR_003058.
FT VARIANT 128 128 Q -> K (in Brest; unstable).
FT /FTId=VAR_003059.
FT VARIANT 129 129 A -> D (in J-Guantanamo; unstable).
FT /FTId=VAR_003060.
FT VARIANT 130 130 A -> P (in Crete; O(2) affinity up;
FT unstable).
FT /FTId=VAR_003061.
FT VARIANT 130 130 A -> V (in La Desirade; O(2) affinity
FT down; unstable).
FT /FTId=VAR_003062.
FT VARIANT 131 131 Y -> D (in Wien; unstable).
FT /FTId=VAR_003063.
FT VARIANT 131 131 Y -> S (in Nevers).
FT /FTId=VAR_003064.
FT VARIANT 132 132 Q -> E (in Camden/Tokuchi/Motown).
FT /FTId=VAR_003065.
FT VARIANT 132 132 Q -> K (in Shelby/Leslie/Deaconess;
FT unstable).
FT /FTId=VAR_003066.
FT VARIANT 132 132 Q -> P (in Shangai; unstable).
FT /FTId=VAR_003067.
FT VARIANT 132 132 Q -> R (in Sarrebourg; unstable).
FT /FTId=VAR_003068.
FT VARIANT 133 133 K -> N (in Yamagata; O(2) affinity down).
FT /FTId=VAR_003069.
FT VARIANT 133 133 K -> Q (in K-Woolwich).
FT /FTId=VAR_003070.
FT VARIANT 134 134 V -> L (in Extredemura).
FT /FTId=VAR_003071.
FT VARIANT 135 135 V -> E (in North Shore-Caracas;
FT unstable).
FT /FTId=VAR_003072.
FT VARIANT 136 136 A -> E (in Beckman; O(2) affinity down;
FT unstable).
FT /FTId=VAR_003073.
FT VARIANT 136 136 A -> P (in Altdorf; O(2) affinity up;
FT unstable).
FT /FTId=VAR_003074.
FT VARIANT 137 137 G -> D (in Hope; O(2) affinity down;
FT unstable).
FT /FTId=VAR_003075.
FT VARIANT 139 139 A -> P (in Brockton; unstable).
FT /FTId=VAR_003076.
FT VARIANT 140 140 N -> D (in Geelong; unstable).
FT /FTId=VAR_003077.
FT VARIANT 140 140 N -> K (in Hinsdale; O(2) affinity down).
FT /FTId=VAR_003078.
FT VARIANT 140 140 N -> S (in S-Wake; associated with V-6).
FT /FTId=VAR_025335.
FT VARIANT 140 140 N -> Y (in Aurora; O(2) affinity up).
FT /FTId=VAR_003079.
FT VARIANT 141 141 A -> D (in Himeji; unstable; O(2)
FT affinity down).
FT /FTId=VAR_003080.
FT VARIANT 141 141 A -> T (in St Jacques: O(2) affinity up).
FT /FTId=VAR_003081.
FT VARIANT 141 141 A -> V (in Puttelange; polycythemia; O(2)
FT affinity up).
FT /FTId=VAR_003082.
FT VARIANT 142 142 L -> R (in Olmsted; unstable).
FT /FTId=VAR_003083.
FT VARIANT 143 143 A -> D (in Ohio; O(2) affinity up).
FT /FTId=VAR_003084.
FT VARIANT 144 144 H -> D (in Rancho Mirage).
FT /FTId=VAR_003085.
FT VARIANT 144 144 H -> P (in Syracuse; O(2) affinity up).
FT /FTId=VAR_003087.
FT VARIANT 144 144 H -> Q (in Little Rock; O(2) affinity up;
FT dbSNP:rs36020563).
FT /FTId=VAR_003086.
FT VARIANT 144 144 H -> R (in Abruzzo; O(2) affinity up).
FT /FTId=VAR_003088.
FT VARIANT 145 145 K -> E (in Mito; O(2) affinity up).
FT /FTId=VAR_003089.
FT VARIANT 146 146 Y -> C (in Rainier; O(2) affinity up).
FT /FTId=VAR_003090.
FT VARIANT 146 146 Y -> H (in Bethesda; O(2) affinity up).
FT /FTId=VAR_003091.
FT VARIANT 147 147 H -> D (in Hiroshima; O(2) affinity up).
FT /FTId=VAR_003092.
FT VARIANT 147 147 H -> L (in Cowtown; O(2) affinity up).
FT /FTId=VAR_003093.
FT VARIANT 147 147 H -> P (in York; O(2) affinity up).
FT /FTId=VAR_003094.
FT VARIANT 147 147 H -> Q (in Kodaira; O(2) affinity up).
FT /FTId=VAR_003095.
FT CONFLICT 26 26 Missing (in Ref. 15; ACD39349).
FT CONFLICT 42 42 F -> L (in Ref. 13; AAR96398).
FT HELIX 6 17
FT HELIX 21 35
FT HELIX 37 42
FT HELIX 44 46
FT HELIX 52 57
FT HELIX 59 75
FT TURN 78 80
FT HELIX 82 95
FT HELIX 102 119
FT HELIX 120 122
FT HELIX 125 143
FT HELIX 144 146
SQ SEQUENCE 147 AA; 15998 MW; A31F6D621C6556A1 CRC64;
MVHLTPEEKS AVTALWGKVN VDEVGGEALG RLLVVYPWTQ RFFESFGDLS TPDAVMGNPK
VKAHGKKVLG AFSDGLAHLD NLKGTFATLS ELHCDKLHVD PENFRLLGNV LVCVLAHHFG
KEFTPPVQAA YQKVVAGVAN ALAHKYH
//

MIM 140700
*RECORD*
*FIELD* NO
140700
*FIELD* TI
#140700 HEINZ BODY ANEMIAS
*FIELD* TX
A number sign (#) is used with this entry because Heinz body anemia is
read moreobserved with several mutations in either the alpha-globin (HBA; 141800)
or the beta-globin (HBB; 141900) gene.

This is a form of nonspherocytic hemolytic anemia of Dacie type I (in
vitro autohemolysis is not corrected by added glucose). After
splenectomy, which has little benefit, basophilic inclusions called
Heinz bodies are demonstrable in the erythrocytes. Before splenectomy,
diffuse or punctate basophilia may be evident. Most of these cases are
probably instances of hemoglobinopathy. The hemoglobin demonstrates heat
lability. Specific defects of the beta-globin gene have been
demonstrated as the basis of Heinz body anemia associated with Hb
Bruxelles (141900.0033), Hb Hammersmith (141900.0100), Hb Indianapolis
(141900.0117), Hb St. Louis (141900.0268), and Hb Tacoma (141900.0278).
Hb Toyama (141800.0152) is an example of a Heinz body anemia due to
mutation in an alpha-globin gene. Heinz bodies are observed also with
the Ivemark syndrome (asplenia with cardiovascular anomalies; 208530).

Rees et al. (1996) reinvestigated the patient who was the subject of the
first description of idiopathic Heinz body anemia (Cathie, 1952) and who
was subsequently shown to have hemoglobin Bristol (141900.0030). The
patient was a 5-year-old boy with anemia from birth and no obvious
precipitating toxic agents. The child was first seen at age 16 months,
when he was jaundiced, with a hemoglobin of 7 g/dl, punctate basophilia,
and 37% reticulocytes. A diagnosis of congenital achloruric jaundice was
made and the spleen removed. He received blood transfusions regularly
until he was 15, when they were stopped with no adverse effects. At the
time of the report by Rees et al. (1996), the patient was 47 years old
and in good health. His steady-state hemoglobin was 7.5 g/dl. He had
suffered one hemolytic crisis following food poisoning in 1991 but did
not need a transfusion. He had 2 subarachnoid hemorrhages in his
twenties, with no residual deficit. He had valvular heart disease
following rheumatic fever at age 16. None of his relatives, including
parents and 5 sibs, suffered from hemolysis or anemia. The 2 unrelated
patients studied by Rees et al. (1996) were the Japanese patients of
Ohba et al. (1985).

Severe Heinz body anemia, in addition to methemoglobinemia, is
associated with Hb St. Louis (140900.0268).

*FIELD* SA
Dacie et al. (1964)
*FIELD* RF
1. Cathie, I. A. B.: Apparent idiopathic Heinz body anaemia. Great
Ormond Street J. 2: 43-48, 1952.

2. Dacie, J. V.; Grimes, A. J.; Meisler, A.; Steingold, L.; Hemsted,
E. H.; Beaven, G. H.; White, J. C.: Hereditary Heinz-body anaemia.
A report of studies on five patients with mild anaemia. Brit. J.
Haemat. 10: 388-402, 1964.

3. Ohba, Y.; Matsuoka, M.; Miyaji, T.; Shibuya, T.; Sakuragawa, M.
: Hemoglobin Bristol or beta 67 (E11) val-to-asp in Japan. Hemoglobin 9:
79-85, 1985.

4. Rees, D. C.; Rochette, J.; Schofield, C.; Green, B.; Morris, M.;
Parker, N. E.; Sasaki, H.; Tanaka, A.; Ohba, Y.; Clegg, J. B.: A
novel silent posttranslational mechanism converts methionine to aspartate
in hemoglobin Bristol (beta-67(E11) val-met-to-asp). Blood 88: 341-348,
1996.

*FIELD* CS

Heme:
Nonspherocytic hemolytic anemia;
Heinz bodies in erythrocytes after splenectomy

Lab:
Heat-labile hemoglobin

Inheritance:
Autosomal dominant

*FIELD* CN
Ada Hamosh - updated: 6/15/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 08/12/2011
alopez: 4/19/2005
carol: 6/27/1999
carol: 6/15/1999
mimadm: 9/24/1994
carol: 4/14/1992
supermim: 3/16/1992
carol: 1/17/1992
carol: 10/25/1991
carol: 10/21/1991

MIM 141900
*RECORD*
*FIELD* NO
141900
*FIELD* TI
+141900 HEMOGLOBIN--BETA LOCUS; HBB
METHEMOGLOBINEMIA, BETA-GLOBIN TYPE, INCLUDED;;
read moreERYTHREMIA, BETA-GLOBIN TYPE, INCLUDED
*FIELD* TX

DESCRIPTION

The alpha (HBA1, 141800; HBA2, 141850) and beta (HBB) loci determine the
structure of the 2 types of polypeptide chains in adult hemoglobin, HbA.
Mutant beta globin that sickles causes sickle cell anemia (603903).
Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of
detectable beta globin causes beta-plus-thalassemia. For clinical
purposes, beta-thalassemia (613985) is divided into thalassemia major
(transfusion dependent), thalassemia intermedia (of intermediate
severity), and thalassemia minor (asymptomatic).

GENE STRUCTURE

Fine detail of both the mouse (Miller et al., 1978) and the human
beta-globin gene was determined in the 1970s (Flavell et al., 1978). The
mouse beta-globin gene is interrupted by 2 intervening sequences of DNA
that divide it into 3 discontinuous segments. The entire gene, including
the coding, intervening and untranslated regions, is transcribed into a
colinear 15S mRNA precursor. Because mature globin mRNA is smaller (10S)
and does not contain the intervening sequences, the 15S precursor must
be processed.

Using restriction endonucleases and recombinant DNA techniques, Flavell
et al. (1978) prepared a map of the human beta- and delta- (142000)
globin genes. The beta-globin gene contains a nonglobin DNA insert about
800-1000 basepairs in length, present within the sequence coding for
amino acids 101-120. A similar untranscribed sequence may be present in
the delta gene.

MAPPING

Use of a combination of somatic cell hybridization and hybridization of
DNA probes permitted assignment of the beta hemoglobin locus to
chromosome 11 (Deisseroth et al., 1978). Parallel experiments showed
that the gamma globin genes (HBG1, 142200; HBG2, 142250) are also on
chromosome 11, a result to be expected from other data indicating
linkage of beta and gamma.

Flavell et al. (1978) found that the distance between the beta and delta
genes is about 7,000 nucleotide pairs and that the delta gene is to the
5-prime side of the beta gene, as predicted by other evidence.
Polymorphism was found at the third nucleotide of the codon for amino
acid number 50 (Wilson et al., 1977).

The order of the genes in the beta-globin cluster was proved by
restriction enzyme studies (Fritsch et al., 1979); starting with the
5-prime end, the order is gamma-G--gamma-A--delta--beta--Hpa I. By
'liquid' molecular hybridization, Haigh et al. (1979) studied mouse-man
hybrid rearrangements involving chromosome 11 and assigned the
nonalpha-globin cluster to the region 11p11-p15.

Housman et al. (1979) concluded from study of Chinese-hamster ovary cell
lines containing chromosome 11 or selected parts thereof that the beta
hemoglobin complex (NAG, nonalpha-globin genes) is in interband
p1205-p1208.

Lebo et al. (1981) studied the linkage between 2 restriction
polymorphisms, the HpaI polymorphism on the 3-prime side of the
beta-globin gene and the SacI polymorphism on the 5-prime side of the
insulin gene. They found 4 recombinants in 34 meioses (12%), giving 90%
confidence limits for the interval as 6-22 cM.

From in situ hybridization studies, Morton et al. (1984) concluded that
the beta-globin gene is situated at 11p15. Their studies included a
t(7;11)(q22;p15) in which the beta-globin locus appeared to be at the
junction point. Interest relates to the translocation cell line coming
from a patient with erythroleukemia and the fact that the ERBB oncogene
(131550) is located on chromosome 7 (7pter-q22).

By high-resolution chromosome sorting of human chromosomes carrying
segments of chromosome 11 and by spot blotting with various
gene-specific probes, Lebo et al. (1985) concluded that the loci for
parathyroid hormone, beta-globin, and insulin are all located on 11p15.

By in situ hybridization studies of chromosome 11 rearrangements,
Magenis et al. (1985) likewise assigned HBB to 11p15. In an addendum,
they referred to studies of a t(7;11) rearrangement that further
narrowed the HBB assignment to 11p15.4-11pter.

By high-resolution cytogenetics and in situ hybridization, Lin et al.
(1985) placed the beta-globin gene in the 11p15.4-p15.5 segment. Through
reanalysis of a Chinese hamster/human cell hybrid that had lost all
human chromosomes except 11, Gerhard et al. (1987) reached the
conclusion that the beta-globin gene complex is located on 11p15 and
that the insulin and HRAS1 genes are located in a segment of DNA
approximately 10 Mb long.

- Pseudogenes

The eta locus is 1 of 5 ancient beta-related globin genes linked in a
cluster, 5-prime--epsilon (142100)--gamma--eta--delta--beta--3-prime,
that arose from tandem duplications (Koop et al., 1986). The eta locus
was embryonically expressed in early eutherians and persisted as a
functional gene in artiodactyls (e.g., goat), but became a pseudogene in
proto-primates and was lost from rodents and lagomorphs. Sequence
studies show that the goat eta gene is orthologous to the pseudogene
located between the gamma and delta loci of primates and called
psi-beta-1. (The Hb beta-1 pseudogene (psi-beta-1) can be symbolized
HBBP or HBBP1.)

GENE FUNCTION

Dye and Proudfoot (2001) performed in vivo analysis of transcriptional
termination for the human beta-globin gene and demonstrated
cotranscriptional cleavage (CoTC). This primary cleavage event within
beta-globin pre-mRNA, downstream of the poly(A) site, is critical for
efficient transcriptional termination by RNA polymerase II (see 180660).
Teixeira et al. (2004) showed that the CoTC process in the human
beta-globin gene involves an RNA self-cleaving activity. They
characterized the autocatalytic core of the CoTC ribozyme and showed its
functional role in efficient termination in vivo. The identified core
CoTC is highly conserved in the 3-prime flanking regions of other
primate beta-globin genes. Functionally, it resembles the 3-prime
processive, self-cleaving ribozymes described for the protein-encoding
genes from the myxomycetes Didymium iridis and Physarum polycephalum,
indicating evolutionary conservation of this molecular process. Teixeira
et al. (2004) predicted that regulated autocatalytic cleavage elements
within pre-mRNAs may be a general phenomenon and that functionally it
may provide an entry point for exonucleases involved in mRNA maturation,
turnover, and, in particular, transcriptional termination.

It is increasingly appreciated that the spatial organization of DNA in
the cell nucleus is a key contributor to genomic function. Simonis et
al. (2006) developed 4C technology (chromosome conformation capture
(3C)-on-chip), which allowed for an unbiased genomewide search for DNA
loci that contact a given locus in the nuclear space. They demonstrated
that active and inactive genes are engaged in many long-range
interchromosomal interactions and can also form interchromosomal
contacts. The active beta-globin locus in the mouse fetal liver
preferentially contacts transcribed, but not necessarily
tissue-specific, loci elsewhere on chromosome 7, whereas the inactive
locus in fetal brain contacts different transcriptionally silent loci. A
housekeeping gene in a gene-dense region on chromosome 8 of the mouse,
Rad23a (600061), formed long-range contacts predominantly with other
active gene clusters, both in cis and in trans, and many of these intra-
and interchromosomal interactions were conserved between the tissues
analyzed. The data demonstrated that chromosomes fold into areas of
active chromatin and areas of inactive chromatin and established 4C
technology as a powerful tool to study nuclear architecture.

Schoenfelder et al. (2010) found that mouse Hbb and Hba associated with
hundreds of active genes from nearly all chromosomes in nuclear foci
that they called 'transcription factories.' The 2 globin genes
preferentially associated with a specific and partially overlapping
subset of active genes. Schoenfelder et al. (2010) also noted that
expression of the Hbb locus is dependent upon Klf1 (600599), while
expression of the Hba locus is only partially dependent on Klf1.
Immunofluorescence analysis of mouse erythroid cells showed that most
Klf1 localized to the cytoplasm and nuclear Klf1 was present in discrete
sites that overlapped with RNAII foci. Klf1 knockout in mouse erythroid
cells specifically disrupted the association of Klf1-regulated genes
within the Hbb-associated network. Klf1 knockout more weakly disrupted
interactions within the specific Hba network. Schoenfelder et al. (2010)
concluded that transcriptional regulation involves a complex
3-dimensional network rather than factors acting on single genes in
isolation.

BIOCHEMICAL FEATURES

- Crystal Structure

Andersen et al. (2012) presented the crystal structure of the dimeric
porcine haptoglobin (140100)-hemoglobin complex determined at
2.9-angstrom resolution. This structure revealed that haptoglobin
molecules dimerize through an unexpected beta-strand swap between 2
complement control protein (CCP) domains, defining a new fusion CCP
domain structure. The haptoglobin serine protease domain forms extensive
interactions with both the alpha- and beta-subunits of hemoglobin,
explaining the tight binding between haptoglobin and hemoglobin. The
hemoglobin-interacting region in the alpha-beta dimer is highly
overlapping with the interface between the 2 alpha-beta dimers that
constitute the native hemoglobin tetramer. Several hemoglobin residues
prone to oxidative modification after exposure to heme-induced reactive
oxygen species are buried in the haptoglobin-hemoglobin interface, thus
showing a direct protective role of haptoglobin. The haptoglobin loop
previously shown to be essential for binding of haptoglobin-hemoglobin
to the macrophage scavenger receptor CD163 (605545) protrudes from the
surface of the distal end of the complex, adjacent to the associated
hemoglobin alpha-subunit. Small-angle x-ray scattering measurements of
human haptoglobin-hemoglobin bound to the ligand-binding fragment of
CD163 confirmed receptor binding in this area, and showed that the rigid
dimeric complex can bind 2 receptors.

MOLECULAR GENETICS

- Beta-Thalassemias

The beta-thalassemias were among the first human genetic diseases to be
examined by means of new techniques of recombinant DNA analysis. In
general, the molecular pathology of disorders resulting from mutations
in the nonalpha-globin gene region is the best known, this elucidation
having started with sickle cell anemia in the late 1940s. Steinberg and
Adams (1982) reviewed the molecular defects identified in thalassemias:
(1) gene deletion, e.g., of the terminal portion of the beta gene (Orkin
et al., 1979); (2) chain termination (nonsense) mutations (Chang and
Kan, 1979; Trecartin et al., 1981); (3) point mutation in an intervening
sequence (Spritz et al., 1981; Westaway and Williamson, 1981); (4) point
mutation at an intervening sequence splice junction (Baird et al.,
1981); (5) frameshift deletion (Orkin and Goff, 1981); (6) fusion genes,
e.g., the hemoglobins Lepore; and (7) single amino acid mutation leading
to very unstable globin, e.g., Hb Vicksburg (beta leu75-to-ter).

Since it had been shown by cDNA-DNA hybridization that some cases of
severe alpha-thalassemia result from deletion of all or most of the
alpha globin genes, Ottolenghi et al. (1975) applied similar techniques
to a study of whether beta genes were present in the forms of
beta-thalassemia with no synthesis of beta chains. They studied material
from persons heterozygous for beta-zero-thalassemia and
delta-beta-thalassemia and concluded that at least one of the haploid
genomes in this patient had a substantially intact beta globin gene. The
beta globin structural gene is intact in beta-zero-thalassemia (Kan et
al., 1975) but deleted in both hereditary persistence of fetal
hemoglobin (Kan et al., 1975) and delta-beta-thalassemia (Ottolenghi et
al., 1975); see 141749.

The possibility that the genetic lesions in beta-plus-thalassemia lie at
splicing sites within intervening sequences of the beta globin gene was
discussed by Maquat et al. (1980). Beta-zero-thalassemia is
heterogeneous. Some cases have absent beta-globin mRNA. Some have a
structurally abnormal beta-globin mRNA, usually in reduced amounts.
Baird et al. (1981) found a nucleotide change at the splice junction at
the 5-prime end of the large intervening sequence (IVS2) as the defect
in 3 cases (1 Italian; 2 Iranian).

In a family of Scottish-Irish descent, Pirastu et al. (1983) studied a
new type of gamma-delta-beta thalassemia. The proposita presented with
hemolytic disease of the newborn which was characterized by microcytic
anemia. Initial restriction enzyme analysis showed no grossly abnormal
pattern, but studies of polymorphic restriction sites and gene dosage
showed extensive deletion of the entire beta-globin cluster. In situ
hybridization with radioactive beta-globin gene probes showed that only
one 11p homolog contained the beta-globin gene cluster. Kazazian et al.
(1982) observed a similar extensive deletion in a Mexican family.

Cai and Kan (1990) demonstrated the usefulness of denaturing gradient
gel electrophoresis for detecting beta-thalassemia mutations and
suggested that it might be a useful nonradioactive means of detecting
mutations in other genetic disorders. Other methods are hybridization
with allele-specific oligonucleotide probes, ribonuclease or chemical
cleavage, and restriction endonuclease analysis. PCR greatly facilitated
implementation of all these detection methods.

Matsuno et al. (1992) invoked possible gene conversion at the chi
sequence near the 5-prime end of exon 2 (codons 31-34) as the
explanation for the finding of a beta-thalassemia mutation common in
southeast Asia (frameshift mutation in codons 41 and 42; see
141900.0326), as well as in Japan, on 2 different restriction frameworks
(haplotypes). They presumed that the 6 families found in Japan with this
particular mutation had inherited it from ancestors who had migrated to
Japan from southeast Asia.

By analysis of family data on 15 restriction site polymorphisms (RSPs),
Chakravarti et al. (1984) identified a 'hotspot' for meiotic
recombination at the 5-prime end of the beta gene. Recombination
leftward (in the 5-prime direction) from a point called chi near the end
of the beta-globin gene is 3 to 30 times the expected rate; in the use
of RSPs in prenatal diagnosis, it had been assumed that a marker 10 kb
from a mutant gene would recombine at a rate of 10(-5) per kb, leading
to a diagnostic error of 1 in 10,000. However, their data suggested the
error rate using 'loci' on opposite sides of chi may be as high as 1 in
312. By a computer search of the DNA sequences of the beta cluster, they
located a chi sequence (5-prime-GCTGGTGG-3-prime) at the 5-prime end of
the second intervening sequence of the beta gene. This chi sequence, a
promoter of generalized recombination in lambda phage, has been found in
high frequency in the mouse genome, especially in immunoglobulin DNA. A
recombinational hotspot has been found in the mouse major
histocompatibility complex.

In a large Amish pedigree, Gerhard et al. (1984) observed an apparent
crossover within the beta-globin gene cluster in the region of the
recombinational 'hotspot' postulated by Chakravarti et al. (1984) on the
basis of linkage disequilibrium in population data. It was also possible
to identify the orientation of the beta-globin cluster vis-a-vis the
centromere: cen--5-prime--epsilon--beta--3-prime--pter.

Camaschella et al. (1988) identified recombination between 2 paternal
chromosomes in a region 5-prime to the beta gene, previously indicated
to contain a 'hotspot' for recombination. The recombination was
identified because in the course of prenatal diagnosis by linkage to
RFLPs, a homozygous beta-thalassemia fetus was misdiagnosed as
beta-thalassemia trait.

In the course of studying an Irish family with beta-thalassemia due to
the Q39X mutation in the HBB gene (141900.0312), Hall et al. (1993)
found a fourth case of recombination in the beta-globin gene cluster.
The event had occurred 5-prime of the polymorphic RsaI site at position
-550 bp upstream of the beta-globin gene mRNA cap site, within the
9.1-kb region shown to be a hotspot for recombination.

Huang et al. (1986) reported the same 'TATA' box mutation leading to the
same nondeletion form of beta-thalassemia in Chinese as had been
reported in American blacks by Antonarakis et al. (1984); see
141900.0379. There are other illustrations indicating that mutations in
the beta-globin gene can recur.

Orkin et al. (1982) developed and applied a new strategy for the
comprehensive analysis of existing mutations in a class of human
disease. They combined analysis of various restriction enzyme
polymorphisms in the beta-globin gene cluster with direct examination of
beta-globin structural genes in Mediterranean persons with
beta-thalassemia. The approach was prompted by the finding that specific
mutant genes are strongly linked to patterns of restriction site
polymorphism (haplotypes) in this region of the genome. They isolated 8
different mutant genes among the 9 different haplotypes represented in
Mediterraneans. Seven of the 8 genes were present in Italians from
various locales in Italy, and 6 in Greeks. Several were previously
unknown mutations, and 1 of these possibly affects transcription. The
strategy is probably applicable to the analysis of heterogeneity in
other diseases of single-copy genes. When linkage analysis can be
performed in the family, the haplotype analysis will be highly useful in
prenatal diagnosis of beta-thalassemia. Indeed, the method of
haplotyping proved highly useful both in tracing the origin of mutations
and in family studies (see Antonarakis et al., 1982). Losekoot et al.
(1992) described a method for rapid detection of beta-globin haplotypes
(referred to by them as framework) by denaturing gradient gel
electrophoresis.

Rosatelli et al. (1987) analyzed the molecular defect in 494 Sardinian
beta-thalassemia heterozygotes. The most prevalent mutation, accounting
for 95.4% of cases, was the nonsense mutation at codon 39 (141900.0312).
The remainder, in decreasing order of frequency, were a frameshift at
codon 6 (2.2%), beta-plus IVS1, nucleotide 110 (0.4%), and beta-plus
IVS2, nucleotide 745 (0.4%). The DNA sequences along the human
beta-globin cluster are highly polymorphic; over 20 polymorphic
restriction endonuclease sites have been described in this 60-kb region.
RFLP haplotypes have been useful in defining various thalassemia
lesions, such as deletions, for prenatal diagnosis of beta-thalassemia,
and for tracing the origin and migration of mutant genes.

Pirastu et al. (1987) found that the predominant beta-thalassemia in
Sardinia, the beta-zero type due to nonsense mutation (CAG-to-TAG) at
beta-39 (141900.0312), resides on 9 different chromosome haplotypes. One
of the haplotypes included a cytosine-to-thymine point mutation 196
nucleotides upstream from the A-gamma-globin gene (142200.0027). The
gamma-A mutation at position -196 is associated with high levels of
production of fetal hemoglobin. The beta-39 nonsense mutation may have
gotten onto the -196 chromosome through crossing-over. A chromosome
carrying such a double mutation could be expected to impart selective
advantage because the beta-thalassemia would protect against malaria
while the increased gamma-globin production would ameliorate the
severity of the beta-thalassemia. A similar mechanism may have been
operative in the case of another haplotype which combined the beta-39
nonsense mutation with triple gamma loci produced by the addition of a
second G-gamma-globin gene. Pirastu et al. (1987) proposed a schema by
which the findings were explained by a single initial mutation with
subsequent crossovers between the 5-prime and 3-prime blocks of genes
producing 6 other chromosomes and then the creation of 2 others by
crossing-over and gene conversion. Additional diversity could have
arisen through other beta-39 mutations. The mutation identified in a
family of northern European origin by Chehab et al. (1986) was of this
type.

Direct sequencing of specific regions of genomic DNA became feasible
with the invention of PCR, which permits amplification of specific
regions of DNA (Church and Gilbert, 1984; Saiki et al., 1986). For
example, Wong et al. (1986) amplified human mitochondrial DNA and
sequenced it directly. Wong et al. (1987) applied a combination of PCR
and direct sequence analysis of the amplified product to the study of
beta-thalassemia in 5 patients whose mutant alleles had not been
characterized. They found 2 previously undescribed mutations along with
3 previously known ones. One new allele was a frameshift at codons
106-107 and the other was an A-to-C transversion at the cap site (+1) of
the beta-globin gene. The latter was the first natural mutation observed
at the cap site (141900.0387).

In a study of beta-thalassemia in Spain, Amselem et al. (1988)
demonstrated the usefulness of the dot-blot hybridization of
PCR-amplified genomic DNA in both rapid population surveys and prenatal
diagnosis. They found 7 different beta-thalassemia mutations. The
nonsense codon 39 accounted for 64%, whereas the IVS1 position 110
mutation (141900.0364), the most common cause of beta-thalassemia in the
eastern part of the Mediterranean basin, was underrepresented (8.5%).
The IVS1 mutation at position 6 (141900.0360) accounted for 15% of the
defects and led to a more severe form of beta(+)-thalassemia than
originally described in most patients with this mutation.

Diaz-Chico et al. (1988) described 2 families, 1 Yugoslavian and 1
Canadian, with heterozygous thalassemia characterized by mild anemia
with severe microcytosis and hypochromia, normal levels of hemoglobin
A(2), and slightly raised hemoglobin F levels. In both families the
condition resulted from large deletions which included all functional
and pseudogenes of the beta-globin gene cluster. The deletion was at
least 148 kb in the Yugoslavian family and 185 kb in the Canadian
family.

Aulehla-Scholz et al. (1989) described a deletion comprising about 300
basepairs in a female heterozygote, resulting in loss of exon 1, part of
IVS1, and the 5-prime beta-globin gene promoter region.

Laig et al. (1989) identified new beta-thalassemia mutations in northern
and northeastern Thailand.

Rund et al. (1991) studied beta-thalassemia among Kurdistan Jews. They
identified 13 distinct mutations among 42 sibships, of which 3 were
previously undescribed. Four of the mutations (see 141900.0331,
141900.0341, 141900.0373, 141900.0383) were unique to Kurdish Jews and
two-thirds of the mutant chromosomes carried the mutations unique to
Kurdish Jews. Haplotype and geographic analyses suggested that
thalassemia in central Kurdistan has evolved from multiple mutational
events. Genetic admixture with the local population appears to be the
primary mechanism of the evolution of thalassemia in Turkish Kurdistan,
whereas there is evidence for a founder effect in Iranian Kurdistan.

Huang et al. (1990) used DNA from dried blood specimens amplified by PCR
to study the distribution of beta-thalassemia mutations in southern,
western, and eastern China.

As indicated by the work of Villegas et al. (1992), Oron et al. (1994),
and Traeger-Synodinos et al. (1996), thalassemia intermedia is caused by
interaction between a triplicated alpha-globin locus (leading to
alpha-globin overproduction) and beta-thalassemia heterozygosity.
Traeger-Synodinos et al. (1996) reported 3 cases of beta-thalassemia
heterozygosity with homozygous alpha-globin gene triplication and 17
beta-thalassemia heterozygotes with a single additional alpha-globin
gene. Garewal et al. (1994) likewise reported 2 patients with a clinical
presentation of thalassemia intermedia due to homozygosity for
alpha-gene triplication and heterozygosity for an HBB gene mutation.

Landin et al. (1996) noted that 34 of 316 beta-globin variants due to
single amino acid substitutions could be caused by more than 1 type of
point mutation at the DNA level. They also noted that 3 beta-globin
variants (Hb Edmonton, Hb Bristol, and Hb Beckman) and 1 alpha-globin
variant (Hb J-Kurosh) could not be produced by a single nucleotide
substitution; 2 substitutions were required.

Several hemoglobin variants were first detected in the course of study
of glycated hemoglobin (HbA1c) in diabetics, e.g., 141900.0429 and
141900.0477. The alternative situation, diagnosis of diabetes during the
performance of hemoglobin electrophoresis for study of anemia, was
observed by Millar et al. (2002).

Sierakowska et al. (1996) found that treatment of mammalian cells stably
expressing the IVS2-654 beta HBB gene (141900.0348) with antisense
oligonucleotides targeted at the aberrant splice sites restored correct
splicing in a dose-dependent fashion, generating correct human
beta-globin mRNA and polypeptide. Both products persisted for up to 72
hours after treatment. The oligonucleotides modified splicing by a true
antisense mechanism without overt unspecific effects on cells growth and
splicing of other pre-mRNAs. This novel approach in which antisense
oligonucleotides are used to restore rather than to downregulate the
activity of the target gene is applicable to other splicing mutants and
is of potential clinical interest.

- Erythrocytosis

Huisman et al. (1996) listed (in their Table 6B) 38 HBB variants causing
erythrocytosis, plus 20 others causing mild erythrocytosis and 1 causing
erythrocytosis in combination with hemolysis. (Some authors, Boyer et
al. (1972), Charache et al. (1975), and Brennan et al. (1982), use
polycythemia rather than erythrocytosis as the designation for the
compensatory increase in red blood cell mass that accompanies
hemoglobins with increased oxygen affinity. The 2 terms must be
considered synonymous. Some, e.g., Hamilton et al. (1969), use
erythremia. Although also a synonym of polycythemia and erythrocytosis,
erythemia has become essentially obsolete.)

- Hereditary Persistence of Fetal Hemoglobin

Part of the mutational repertoire of the beta-globin locus is hereditary
persistence of fetal hemoglobin (HPFH; 141749) due to deletion. Two
types (types I and II) occur in blacks and have as their basis deletion
of the delta and beta loci. An Italian type and an Indian type are
likewise deletion forms of HPFH; see review by Saglio et al. (1986). In
2 Italian brothers with a G-gamma/A-gamma form of hereditary persistence
of fetal hemoglobin, Camaschella et al. (1990) demonstrated a deletion
starting 3.2 kb upstream from the delta gene and ending within the
enhancer region 3-prime to the beta-globin gene. The deletion removed 1
of the 4 binding sites for an erythroid specific transcriptional factor
(NF-E1). It appeared that the residual enhancer element, relocated near
gamma genes, may increase fetal hemoglobin expression.

- Delta-Beta Thalassemia

In the so-called Corfu form of delta-beta-thalassemia, Kulozik et al.
(1988) found that a deletion removed 7,201 basepairs containing part of
the delta-globin gene and sequences upstream. The beta-globin gene
contained a G-to-A mutation at position 5 in IVS1. The gamma-globin gene
promoters were normal. In transfected HeLa cells, a normal message was
produced from the mutated beta-globin gene at a level of approximately
20% of the normal, the remaining 80% being spliced at cryptic sites in
exon 1 and intron 1. This indicated that the mutation in the beta-globin
gene is not the sole cause of the complete absence of hemoglobin A in
this form of thalassemia. Kulozik et al. (1988) concluded that the
7.2-kb deletion contains sequences necessary for the normal activation
of the beta-globin gene. In the homozygous state there is complete
absence of hemoglobin A and hemoglobin A(2) and a high level of
hemoglobin F. Traeger-Synodinos et al. (1991) gave further data on the
Corfu mutation.

- Protection Against Malaria

Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
subjects and transmission experiments involving 60 children and over
6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
variants HbC (141900.0038) and HbS (141900.0243), which are protective
against malaria, are associated with transmission of the parasite from
the human host to the Anopheles mosquito vector. They found that HbC and
HbS were associated with significant 2-fold in vivo (p = 1.0 x 10(-6))
and 4-fold ex vivo (p = 7.0 x 10(-5)) increases of parasite transmission
from host to vector. Gouagna et al. (2010) concluded that human genetic
variation at the HBB locus can influence the efficiency of malaria
transmission, possibly by promoting sexual differentiation of P.
falciparum as a downstream phenotypic event. Alternatively, Gouagna et
al. (2010) suggested that the higher infectivity of individuals with HBB
variants in their study could be due to less frequent use of
antimalarial drugs. In a commentary, Pasvol (2010) noted that little is
known regarding the mechanisms involved in switching from the parasite
asexual stages to the induction of gametogenesis, but that the
hemoglobinopathies may provide a scenario beneficial to both host and
parasite.

- Reviews

Kazazian and Boehm (1988) gave an update on the variety of
beta-thalassemias. Large deletions are a rare cause of beta-thalassemia;
as of early 1989, 63 single nucleotide substitutions or small deletions
and 7 large deletions had been described as the basis of
beta-thalassemia (Kazazian, 1989).

Huisman (1990) provided a list of over 110 different beta-thalassemia
alleles, most of them of the nondeletional type.

Huisman (1992) edited an up-to-date listing of the deletions, mutations,
and frameshifts leading to beta-thalassemia, which had been published 3
times previously, and added a new table on the delta-thalassemias,
prepared by Erol Baysal. Kazazian et al. (1992) tabulated a total of 9
beta-globin mutations producing dominant thalassemia-like phenotypes.
Widespread ethnic derivation was demonstrated.

Krawczak et al. (1992) reviewed the mutational spectrum of single
basepair substitutions in mRNA splice junctions on the basis of 101
different examples of point mutations occurring in the vicinity of
splice junctions and held to be responsible for human genetic disease.
The data comprised 62 mutations at 5-prime splice sites, 26 at 3-prime
splice sites, and 13 that resulted in the creation of novel splice sites
such as HbE. They estimated that up to 15% of all point mutations
causing human genetic disease result in an mRNA splicing defect.

Carver and Kutlar (1995) listed 323 beta-chain variants as of January
1995. This number did not include beta-chain variants with deletions
and/or insertions or those with extended polypeptide chains. Baysal and
Carver (1995) provided an update (eighth edition) of their catalog, or
repository, of beta-thalassemia and delta-thalassemia.

Huisman et al. (1996) provided a syllabus of human hemoglobin variants
listing the characteristics as well as precise molecular change of known
beta-globin mutants; these numbered 335 single-base mutations and 17
variants with 2 amino acid replacements as of January 1996. They also
included hemoglobin variants resulting from fusion of parts of the
beta-chain and delta-chain, variants with elongated beta-chains at both
the C-terminal and N-terminal ends, and variants with small deletions
and/or insertions in the beta-chain. Not included were deletions and
mutations that result in beta-thalassemia, even if such a change, point
mutation, or frameshift occurred in one of the coding regions of the HBB
gene. Information regarding these abnormalities were provided elsewhere,
e.g., Baysal and Carver (1995).

Huisman et al. (1996) stated that 138 of the 146 codons of the HBB gene
have been mutated; 5 mutations are known for 6 codons (22, 67, 97, 121,
143, and 146), 6 mutations for codon 92, and 7 mutations for codon 99.
Most of the mutations have been deduced from the sequence of the amino
acid sequence of the variant protein and the known sequence of the HBB
gene; slightly more than 10% of the mutations have been determined
through DNA sequencing. Occasionally discrepancy was observed, such as
at position 50 and 67 of the beta-globin chain.

- Database of Hemoglobin Variants

Hardison et al. (2002) constructed a web-accessible relational database
of hemoglobin variants and thalassemia mutations called HbVar, in which
old and new data are incorporated. Queries can be formulated based on
fields in the database. For example, tables of common categories of
variants, such as all variants involving the HBA1 gene (141800) or all
those that result in high oxygen affinity, can be assembled. More
precise queries are possible, such as 'all beta-globin variants
associated with instability and found in Scottish populations.'

- Locus Control Region Beta

Cases of gamma-delta-beta thalassemia are known in which the beta gene
is intact but deletion 'in cis' occurs upstream, even at a distance, in
a region designated LCRB. In a remarkable case reported by Curtin et al.
(1985), a deletion extended from the third exon of the G-gamma gene
upstream for about 100 kb. The A-gamma, pseudo-beta, delta, and beta
genes in cis were intact. This malfunction of the beta-globin gene on a
chromosome in which the deletion is located 25 kb away suggests that
chromatin structure and conformation are important for globin gene
expression. In experiments in which the human beta-globin locus was
introduced into the mouse genome, Talbot et al. (1989) found a 6.5-kb
control region which allowed achievement of endogenous levels of
beta-globin expression. The control region included an erythroid
cell-specific DNase I hypersensitive site (HS). Using pulsed field gel
electrophoresis and PCR, Driscoll et al. (1989) found, in a case of
gamma-delta-beta-thalassemia, a de novo deletion on a maternally
inherited chromosome 11 involving about 30 kb of sequences 5-prime to
the epsilon gene. The deletion extended from -9.5 kb to -39 kb 5-prime
of epsilon and included 3 of the 4 DNase I hypersensitive sites (at
-10.9 kb, -14.7 kb, and -18 kb 5-prime of epsilon). The remaining
sequences of the beta-globin complex, including the DNase I
hypersensitive sites at -6.1 kb and all structural genes in cis to the
deletion, were physically intact. Again, a significance of the
hypersensitive sites in regulating globin-gene expression was
demonstrated.

Epsilon-gamma-delta-beta-thalassemias are all caused by deletions of the
beta-globin gene cluster on 11p. At the molecular level, the deletions
fall into 2 categories: group I removes all or a greater part of the
beta-globin cluster, including the beta-globin gene; group II removes
extensive upstream regions leaving the beta-globin gene itself intact
despite which its expression is silenced because of inactivation of the
upstream beta-locus control region. A group I deletion was reported by
Curtin et al. (1985). A group I deletion was reported in a Chilean
family by Game et al. (2003), and an upstream deletion (group II) was
reported in a Dutch family by Harteveld et al. (2003). Rooks et al.
(2005) described 3 novel epsilon-gamma-delta-beta-thalassemia deletions
in 3 English families, referred to as English II, III, and IV to
distinguish them from the family of Curtin et al. (1985), which was also
English (I). Two of the deletions removed the entire beta-globin gene
complex, including a variable number of flanking olfactory receptor
genes.

The significance of the hypersensitive sites to globin gene expression
had also been demonstrated by Grosveld et al. (1987) who achieved high
levels of position-independent beta-gene expression in transgenic mice
with a specially constructed beta-globin minilocus in which 5-prime and
3-prime hypersensitive sequences flanked a beta-globin gene. The
hypersensitive sequences, termed locus-activating regions (LARs), are
erythroid-tissue-specific and developmentally stable. Curtin et al.
(1989) performed experiments similar to those of Grosveld et al. (1987)
with like results. (A similar positive control region for the cluster of
alpha-globin genes was deduced by Hatton et al. (1990) on the basis of
deletion in a case of alpha-thalassemia; see 141800.) See 187550 for
evidence of an unlinked remote regulator of HBB gene expression. Townes
and Behringer (1990) reviewed the topic of the locus activating region.
They presented a model for developmental control of human globin gene
expression (see their Figure 2). With respect to the cap site of the
human epsilon-globin gene, LAR site I is located at position -6.1 kb;
site II, at -10.9 kb; site III, at -14.7 kb; and site IV, at -18 kb.
Moon and Ley (1990) cloned murine DNA sequences homologous to the human
LAR site II. These sequences are linked to the mouse beta-globin gene
cluster in the same basic arrangement as the human beta-globin gene
cluster. Furthermore, the 2 LARs share 70% identical sequence and
several enhancer-type functions. LAR sequences are almost certainly not
confined to the human beta-globin locus. The investigators stated that
these sequences may be critical components of any gene family that
comprises multiple members that are regulated differently during
development.

Perichon et al. (1993) demonstrated interethnic polymorphism of 1
segment of the LCRB region in sickle cell anemia patients. Distinct
polymorphic patterns of a simple sequence repeat were observed in strong
linkage disequilibrium with each of the 5 major beta-S haplotypes.

Studies by Grosveld et al. (1987) and by Blom van Assendelft et al.
(1989) established that 6 DNase I hypersensitive sites flank the globin
genes. One HS site is located 20 kb downstream of the beta-globin
cluster and 5 HS sites are located 6-22 kb upstream within the locus
control region (LCR). Peterson et al. (1996) examined the effects of
deletion of the LCR 5-prime HS3 element and the 5-prime HS2 element on
globin gene expression by recombining a 2.3-kb deletion of 5-prime HS3
or a 1.9-kb deletion of 5-prime HS2 into a beta-globin locus YAC, which
was then used to produce transgenic mice. When the LCR 5-prime HS3
element is deleted there is decreased expression of epsilon-globin in
the yolk sac. Deletion of 5-prime HS2 resulted in a minor but
statistically significant decrease in epsilon-, gamma-, and beta-globin
expression. From these results Peterson et al. (1996) concluded that
there is functional redundancy among the HS sites. The effects of the
5-prime HS3 deletion on epsilon-globin gene expression led them to
conclude that specific interactions between the HSs and the globin genes
underlie activation of globin genes during specific stages of
development.

Epner et al. (1998) deleted the murine beta-globin LCR from its native
chromosomal location. The approximately 25-kb deletion eliminated all
sequences and structures homologous to those defined as the human LCR.
In differentiated embryonic stem cells and erythroleukemia cells
containing the LCR-deleted chromosome, DNase I sensitivity of the
beta-globin domain was established and maintained, developmental
regulation of the locus was intact, and beta-like globin RNA levels were
reduced 5 to 25% of normal. Thus, in the native murine beta-globin
locus, the LCR was necessary for normal levels of transcription, but
other elements were sufficient to establish the open chromatin
structure, transcription, and developmental specificity of the locus.
These findings suggest a contributory rather than dominant function for
the LCR in its native location.

Bauchwitz and Costantini (2000) quantified the effects of beta-globin
sequence modifications on epsilon-, gamma-, and delta-globin levels in
transgenic mice. Embryonic day 11.5 primitive erythroid cells showed a
large increase in epsilon-globin in the absence of the beta-globin gene,
which is weakly expressed at that stage of development. Embryonic day
17.5 fetal liver and adult erythroid cells, in which beta-globin
expression approaches its maximum, showed only a small stimulation of
gamma- and delta-globin levels in the absence of beta-globin sequence.
Analysis of erythroid colonies produced by in vitro differentiation of
embryonic stem cells indicated that the absence of the human beta-globin
gene had no effect on gamma-globin expression. The authors concluded
that competitive influences need not be linked directly to
transcriptional level or distance from the LCR, and that the large
increases in gamma-globin levels seen in some human deletional
beta-thalassemias and hereditary persistence of fetal hemoglobin
conditions are most likely due to effects other than loss of beta-globin
competition. In transgenic mice with beta-globin sequences inserted
between epsilon and the LCR in a beta-locus, the expression of epsilon-,
gamma-, and delta-globins suggested that stage-specific sensitivity to
loss of LCR activity may be a more important parameter than position
relative to the LCR.

Alami et al. (2000) created a yeast artificial chromosome containing an
unmodified human beta-globin locus, and introduced it into transgenic
mice at various locations in the genome. The locus was not subject to
detectable stable position effects but did undergo mild-to-severe
variegating position effects at 3 of the 4 noncentromeric integration
sites tested. The distance and the orientation of the LCR relative to
the regulated gene contributed to the likelihood of variegating position
effects, and affected the magnitude of its transcriptional enhancement.
DNaseI hypersensitive site (HSS) formation varied with the proportion of
expressing cells (variegation), rather than the level of gene
expression, suggesting that silencing of the transgene may be associated
with a lack of HSS formation in the LCR region. The authors concluded
that transcriptional enhancement and variegating position effects are
caused by fundamentally different but interdependent mechanisms.

Navas et al. (2002) generated transgenic mouse lines carrying a
beta-globin locus YAC lacking the LCR to determine if the LCR is
required for globin gene activation. Beta-globin gene expression was
analyzed by RNase protection, but no detectable levels of epsilon-,
gamma-, and beta-globin gene transcripts were produced at any stage of
development. Lack of gamma-globin gene expression was also seen in a
beta-YAC transgenic mouse carrying a gamma-globin promoter mutant that
causes hereditary persistence of fetal hemoglobin (see 142200.0026) and
an HS3 core deletion that specifically abolishes gamma-globin gene
expression during definitive erythropoiesis. The authors concluded that
the presence of the LCR is a minimum requirement for globin gene
expression.

Navas et al. (2003) assessed the contribution of the GT6 motif within
HS3 of the LCR on downstream globin gene expression by mutating GT6 in a
beta-globin locus YAC and measuring the activity of beta-globin genes in
GT6-mutated beta-YAC transgenic mice. They found reduced expression of
epsilon- and gamma-globin genes during embryonic erythropoiesis. During
definitive erythropoiesis, gamma-globin gene expression was
significantly reduced while beta-globin gene expression was virtually
indistinguishable from that of wildtype controls. Navas et al. (2003)
concluded that the GT6 motif is required for normal epsilon- and
gamma-globin gene expression during embryonic erythropoiesis and for
gamma-globin gene expression during definitive erythropoiesis in the
fetal liver.

Bottardi et al. (2005) noted that abnormal epigenetic regulation of gene
expression contributes significantly to a variety of human pathologies
including cancer. Deletion of HS2 at the human beta-globin locus control
region can lead to abnormal epigenetic regulation of globin genes in
transgenic mice. The authors used 2 HS2-deleted transgenic mouse lines
as a model to demonstrate that heritable alteration of chromatin
organization at the human beta-globin locus in multipotent hematopoietic
progenitors can contribute to the abnormal expression of the beta-globin
gene in mature erythroid cells. This alteration was characterized by
specific patterns of histone covalent modifications that were inherited
during erythropoiesis and, moreover, was plastic because it could be
reverted by transient treatment with a histone deacetylase inhibitor.
Bottardi et al. (2005) concluded that aberrant epigenetic regulation can
be detected and modified before tissue-specific gene transcription.

- Note Regarding the Allelic Variants Section

In the allelic variants listed below, as well as in the allelic variants
listed under the other globin genes, the codon count begins with the
first amino acid of the mature protein because a large portion of the
variants were characterized on the basis of a protein rather than the
gene itself. It is more customary for the count to begin with the
methionine initiator codon as number one. Thus, the HbS mutation
(141900.0243) is designated glu6-to-val; in the gene based system of
counting now used, it would be designated glu7-to-val. Some
inconsistency is represented by the fact that some initiator mutations
in the globin genes are indicated by a system counting from the
initiator methionine; e.g., beta-thalassemia due to met1-to-ile
(141900.0430).

ANIMAL MODEL

Ciavatta et al. (1995) created a mouse model of beta-zero-thalassemia by
targeted deletion of both adult beta-like globin genes, beta(maj) and
beta(min), in mouse embryonic stem cells. Heterozygous animals derived
from the targeted cells were severely anemic with dramatically reduced
hemoglobin levels, abnormal red cell morphology, splenomegaly, and
markedly increased reticulocyte counts. Homozygous animals died in
utero; however, heterozygous mice were fertile and transmitted the
deleted allele to progeny. The anemic phenotype was completely rescued
in progeny derived from mating beta-zero-thalassemic animals with
transgenic mice expressing high levels of human hemoglobin A. The
authors suggested that beta-zero-thalassemic mice could be used to test
genetic therapy for beta-zero-thalassemia and could be bred with
transgenic mice expressing high levels of hemoglobin S to produce an
improved mouse model of sickle cell disease.

Hemoglobin disorders were among the first to be considered for gene
therapy. Transcriptional silencing of genes transferred into
hematopoietic stem cells, however, posed one of the most significant
challenges to its success. If the transferred gene is not completely
silenced, a progressive decline in gene expression as mice age often is
encountered. These phenomena were observed to various degrees in mouse
transplant experiments using retroviral vectors containing a human
beta-globin gene, even when cis-linked to locus control region
derivatives. Kalberer et al. (2000) investigated whether ex vivo
preselection of retrovirally transduced stem cells on the basis of
expression of the green fluorescent protein driven by the CpG island
phosphoglycerate kinase (311800) promoter could ensure subsequent
long-term expression of a cis-linked beta-globin gene in the erythroid
lineage of transplanted mice. They observed that 100% of 7 mice
engrafted with preselected cells concurrently expressed human
beta-globin and green fluorescent protein in 20 to 95% of their red
blood cells for up to 9.5 months posttransplantation, the longest time
point assessed. This expression pattern was successfully transferred to
secondary transplant recipients. In the presence of the beta-locus
control region hypersensitivity site 2 alone, human beta-globin mRNA
expression levels ranged from 0.15 to 20% with human beta-globin chains
detected by HPLC. Neither the proportion of positive blood cells nor the
average expression levels declined with time in translated recipients.

Persons and Nienhuis (2000) discussed the background of the work by
Kalberer et al. (2000), including position effect variegation (PEV).
Both PEV and silencing mechanisms may act on a transferred globin gene
residing in chromatin outside of the normal globin locus during the
important terminal phases of erythroblast development when globin
transcripts normally accumulate rapidly despite heterochromatization and
shutdown of the rest of the genome.

HISTORY

By autoradiography using heavy-labeled hemoglobin-specific messenger
RNA, Price et al. (1972) found labeling of a chromosome 2 and a group B
chromosome. They concluded, incorrectly as it turned out, that the
beta-gamma-delta linkage group was on a group B chromosome since the
zone of labeling was longer on that chromosome than on chromosome 2
(which by this reasoning was presumed to carry the alpha locus or loci).
Study of a case of the Wolf-Hirschhorn syndrome (4p-) suggested that the
B group chromosome involved is chromosome 4. Barbosa et al. (1975)
excluded a recombination fraction of less than 0.30 for MN and Hb-beta.

McCurdy et al. (1975) thought the beta locus in some persons might be
duplicated; they observed a black woman who had hemoglobin A and 2
different variant hemoglobins, each with a beta-globin change. One of
these, however, proved to be a posttranslational change (Charache et
al., 1977). El-Hazmi et al. (1986) suggested that the presence of 2
beta-globin genes might account for the finding of triple HpaI fragments
in a case of sickle cell anemia. They explained its origin by unequal
crossing-over.

Housman et al. (1979) used a panel of hybrid hamster-human cells deleted
by x-ray and selected by a double antibody technique (the method of Kao,
Jones, and Puck) to assign the NAG cluster to 11p12, between LDHA
distally and ACP2 proximally. The orientation of the cluster in relation
to the centromere was not known.

Although some workers have put the insulin (176730), beta-globin, and
HRAS (190020) genes on 11p15, Chaganti et al. (1985) located these
differently by in situ hybridization to meiotic chromosomes: INS,
11p14.1; HRAS, 11p14.1; HBB, 11p11.22; and PTH (not previously
assigned), 11p11.21.

*FIELD* AV
.0001
HEMOGLOBIN AALBORG
HBB, GLY74ARG

See Williamson et al. (1990).

.0002
HEMOGLOBIN ABRUZZO
HBB, HIS143ARG

See Tentori et al. (1972), Chiancone et al. (1974), and Zhao et al.
(1990).

.0003
HEMOGLOBIN AGENOGI
HBB, GLU90LYS

See Miyaji et al. (1966). As indicated by Corso et al. (1990), carriers
of the mutation had been found in only 3 families, an American black, a
Sicilian, and a Hungarian family, suggesting independent origins of the
mutation. Corso et al. (1990) described another Sicilian family in which
5 members carried Hb Agenogi; in 1, it was associated with
beta-zero-thalassemia. The proposita, a 40-year-old woman with 2
children, came to attention because of mild chronic anemia and biliary
colic due to gallstones.

Noguera et al. (2002) described Hb Agenogi in an Argentinian patient
with Syrian and Hungarian ancestry. The mutation had previously been
described in only 5 families, one of which was from Hungary.

.0004
HEMOGLOBIN ALABAMA
HBB, GLN39LYS

See Brimhall et al. (1975).

.0005
HEMOGLOBIN ALAMO
HBB, ASN19ASP

See Lam et al. (1977) and Arends et al. (1987).

.0006
HEMOGLOBIN ALBERTA
HBB, GLU101GLY

See Mant et al. (1977), Stinson (1977), and Wong et al. (1978).

.0007
HEMOGLOBIN ALTDORF
HBB, ALA135PRO

See Marti et al. (1976).

.0008
HEMOGLOBIN ANDREW-MINNEAPOLIS
HBB, LYS144ASN

See Zak et al. (1974). Hebbel et al. (1978) used this hemoglobin to make
ingenious observations on adaptation of humans to high altitudes.

.0009
HEMOGLOBIN ANKARA
HBB, ALA10ASP

See Arcasoy et al. (1974) and Harano et al. (1981).

.0010
HEMOGLOBIN ARLINGTON PARK
HBB, GLU6LYS AND LYS95GLU

May have arisen either through a second mutation in a person with HbC or
Hb N(Baltimore), or through crossing-over in a person who was
heterozygous for both mutant hemoglobins. See Adams and Heller (1977).

.0011
HEMOGLOBIN ATHENS-GEORGIA
HEMOGLOBIN WACO
HBB, ARG40LYS

See Brown et al. (1976) and Moo-Penn et al. (1977).

.0012
HEMOGLOBIN ATLANTA
HBB, LEU75PRO

Unstable hemoglobin. See Hubbard et al. (1975) and Brennan et al.
(1983).

.0013
HEMOGLOBIN ATLANTA-COVENTRY
HBB, LEU75PRO AND LEU141DEL

Brennan et al. (1986) described a 25-year-old man with congenital
hemolytic anemia who was found to have the mutation of Hb Atlanta
(beta75 leu-to-pro) and that of Hb Coventry (beta141 leu deleted) in the
same beta-globin chain along with a normal beta-globin chain and a
beta-globin chain with only the Hb Atlanta mutation. They stated that
this is the sixth known example of 2 changes in 1 beta chain. They
postulated that the doubly abnormal beta-globin was a beta-delta globin
originating by a Lepore-type-mechanism. Brennan et al. (1992) found on
restudy that leu141 was in fact not deleted but replaced by a novel
amino acid which they suggested was hydroxyleucine; they proposed that
the change resulted from posttranslational oxidation of leu141 as a
consequence of perturbation of the haem environment caused by the
leu75-to-pro mutation. The finding was consistent with the report of
George et al. (1992) who found no evidence of deletion of leu141 in
genomic DNA. The heterozygous patients have 3 hemoglobins: HbA, Hb
Atlanta, and Hb Atlanta-Coventry. The last 2 are the products of a
single gene. A similar situation obtains with Hb Vicksburg
(141900.0293), in which deletion of leu75 is not coded for in genomic
DNA. Coleman et al. (1988) posited somatic mutation in that instance;
however, a mechanism similar to that with Hb Atlanta-Coventry is
possible.

.0014
HEMOGLOBIN AUSTIN
HBB, ARG40SER

See Moo-Penn et al. (1977).

.0015
HEMOGLOBIN AVICENNA
HBB, ASP47ALA

See Rahbar et al. (1979).

.0016
HEMOGLOBIN BARCELONA
HBB, ASP94HIS

See Wajcman et al. (1982). This is a high oxygen affinity hemoglobin
variant.

.0017
HEMOGLOBIN BAYLOR
HBB, LEU81ARG

See Schneider et al. (1977).

.0018
HEMOGLOBIN BEIRUT
HBB, VAL126ALA

See Strahler et al. (1983) and Blibech et al. (1986).

.0019
HEMOGLOBIN BELFAST
HBB, TRP15ARG

See Kennedy et al. (1974).

Galanello et al. (2004) reported the sixth occurrence of Hb Belfast, a
change of codon 15 of the HBB gene from TGG (trp) to AGG (arg) (trp15 to
arg; W15R), in a large Italian family with 9 affected members. The
oxygen affinity of the isolated variant was increased. The clinical
phenotype was silent or very mild, the only clinical finding being an
intermittent moderate jaundice.

.0020
HEMOGLOBIN BEOGRAD
HEMOGLOBIN D (CAMPERDOWN)
HBB, GLU121VAL

See Efremov et al. (1973), Wilkinson et al. (1975), and Ruvidic et al.
(1975).

Akar et al. (1995) described a dual restriction enzyme digestion
protocol for discriminating between Hb Beograd and Hb D (Los Angeles)
(glu121 to gln) when they occur in the same population. Both of these
variants migrate like HbS on cellulose acetate electrophoresis. Hb O
(Arab) (glu121 to lys; 141900.0202) represents no problem because that
variant migrates differently on cellulose acetate electrophoresis. Also,
the glu121-to-ter mutation (141900.0314) represents no problem because
it is associated with a thalassemia phenotype. Other codon 121 mutations
are Hb D (Neath) (glu121 to-ala; 141900.0445) and Hb St. Francis (glu121
to gly; 141900.0412).

.0021
HEMOGLOBIN BETH ISRAEL
HBB, ASN102SER

Like Hb Kansas, this variant was associated with clinically evident
cyanosis due to very low oxygen affinity (Nagel et al., 1976). (The
hemoglobins M are not the only anomalous hemoglobins associated with
cyanosis.)

.0022
HEMOGLOBIN BETHESDA
HBB, TYR145HIS

See Hayashi et al. (1971), Adamson et al. (1972), Bunn et al. (1972),
and Schmidt et al. (1976). See Hb Rainier.

.0023
HEMOGLOBIN BICETRE
HBB, HIS63PRO

See Wajcman et al. (1976) and Miller et al. (1986).

.0024
HEMOGLOBIN BOLOGNA
HBB, LYS61MET

See Marinucci et al. (1981).

.0025
HEMOGLOBIN BORAS
HBB, LEU88ARG

See Hollender et al. (1969) and Bird et al. (1987).

.0026
HEMOGLOBIN BOUGARDIREY-MALI
HBB, GLY119VAL

See Chen-Marotel et al. (1979).

.0027
HEMOGLOBIN BREST
HBB, GLN127LYS

See Baudin-Chich et al. (1988).

.0028
HEMOGLOBIN BRIGHAM
HBB, PRO100LEU

This variant is a cause of erythrocytosis. See Lokich et al. (1973).

.0029
HEMOGLOBIN BRISBANE
HEMOGLOBIN GREAT LAKES
HBB, LEU68HIS

See Brennan et al. (1981), Rahbar et al. (1981), and Williamson et al.
(1983).

.0030
HEMOGLOBIN BRISTOL
HBB, VAL67MET-TO-ASP

See Steadman et al. (1970) and Ohba et al. (1985).

Rees et al. (1996) reinvestigated the patient who was the subject of the
first description of idiopathic Heinz body anemia (140700) (Cathie,
1952) and who was subsequently shown to have hemoglobin Bristol. Using
both DNA and protein analysis, they showed that the original
characterization of hemoglobin Bristol as val67 to asp was incorrect, in
that a silent posttranslational modification of met to asp was mistaken
for the primary mutation, which is, in fact, val67 to met. They also
restudied 2 subsequent patients reported as having hemoglobin Bristol
following protein sequencing in whom the same confusion occurred. They
were able to describe a novel posttranslational modification in which
the variant methionine amino acid residue is converted to an aspartate,
probably catalyzed by the neighboring heme group and oxygen. The study
emphasized the importance of analyzing both protein and DNA to
characterize fully hemoglobin variants. Identification of the lesion as
val67 to asp was made by Steadman et al. (1970).

Although DNA codes for 20 primary amino acids, more than 140 different
residues have been identified in proteins due to varied
posttranslational modifications. Most are relatively simple reactions
involving enzymatic modification of the site change of amino acids to
enhance or determine the properties of the particular protein; these
processes include acetylation, phosphorylation, hydroxylation, and
glycation. There are also a number of posttranslational modifications of
hemoglobin A, such as glycation and carbamoylation, but these are due
mostly to nonspecific metabolic affects that alter the chemical
environment of the hemoglobin, rather than direct results of the
properties of the hemoglobin itself. Unstable hemoglobin variants are
characterized by the reduced solubility of the hemoglobin tetramer in
the red cell in peripheral blood. Most result from mutations of amino
acids in key positions, for example, heme- or alpha-beta contact points.
Mutations can also alter the structure of the molecule such that
posttranslational changes can occur, either of the variant amino acid
itself or of other residues exposed by changes in the conformation of
the molecule. More rarely, so-called silent modifications occur, in
which 1 primary amino acid is converted to another primary amino acid.
This is what happened in the case of hemoglobin Bristol. The
modification of beta-143 leu, such that it appears to be deleted on
protein sequencing, in hemoglobin Atlanta-Coventry (141900.0013) is the
result of posttranslational modification, possibly from leucine to
hydroxyleucine, as a result of the primary mutation that effects the
heme surface. The same apparent deletion of leu-149 is observed with Hb
Christchurch (141900.0049) and with Hb Manukau (141900.0438), which is
also a mutation of val67 (val67 to gly). There are 6 reported hemoglobin
variants in which deamidation of an asparaginyl residue to an aspartate
occurs as a silent posttranslational modification: these include
hemoglobin Osler (141900.0211). The posttranslational change from
methionine to aspartate was the first example to be described (Rees et
al., 1996); the exact mechanism of the change is not clear.

.0031
HEMOGLOBIN BRITISH COLUMBIA
HBB, GLU101LYS

See Jones et al. (1977) and Stinson (1984).

.0032
HEMOGLOBIN BROCKTON
HBB, ALA138PRO

See Moo-Penn et al. (1980, 1988) and Ulukutlu et al. (1989). Negri
Arjona et al. (1992) found a GCT (ala)-to-CCT (pro) mutation in codon
138 in a 6-year-old Spanish girl with chronic hemolytic anemia requiring
transfusion. The patient showed Heinz bodies. Her parents and a brother
were normal, indicating that her disorder represented a new mutation.

Tsoi et al. (1998) identified Hb Brockton in a 9-year-old Chinese boy
with long-standing hemolysis. As in previous reports, the mutation
occurred de novo. Tsoi et al. (1998) noted that the patient also had
moyamoya disease (see 252350).

.0033
HEMOGLOBIN BRUXELLES
HEINZ BODY HEMOLYTIC ANEMIA
HBB, PHE41DEL OR PHE42DEL

Blouquit et al. (1989) demonstrated that hemoglobin Bruxelles, a
beta-globin variant associated with severe congenital Heinz body anemia,
has a deletion of 1 of the 2 adjacent phenylalanines, either phe41 or
phe42. Other deletions affecting the phe41 or phe42 have been described.
The nucleotide sequence of normal beta-globin mRNA is highly repetitive
in the region of codons 41 to 46. Blouquit et al. (1989) suggested that
the mutation originated through a frameshift mechanism.

.0034
HEMOGLOBIN BRYN MAWR
HEMOGLOBIN BUENOS AIRES
HBB, PHE85SER

See Bradley et al. (1972), Lehmann (1973), and Weinstein et al. (1973).

.0035
HEMOGLOBIN BUNBURY
HBB, ASP94ASN

See Como et al. (1983). This is a high oxygen affinity hemoglobin
variant.

.0036
HEMOGLOBIN BURKE
HBB, GLY107ARG

See Turner et al. (1976) and Kobayashi et al. (1986).

.0037
HEMOGLOBIN BUSHWICK
HBB, GLY74VAL

See Rieder et al. (1974), Ohba et al. (1985), and Efremov et al. (1987).

.0038
HEMOGLOBIN C
MALARIA, RESISTANCE TO, INCLUDED
HBB, GLU6LYS

See Itano and Neel (1950), Neel et al. (1953), Ranney et al. (1953),
Hunt and Ingram (1959), Smith and Krevans (1959), Baglioni and Ingram
(1961), River et al. (1961), and Fabry et al. (1981).

By restriction haplotyping, Boehm et al. (1985) concluded that the
beta-C-globin gene in blacks had a single origin followed by spread of
the mutation to other haplotypes through meiotic recombination 5-prime
to the beta-globin gene. On 22 of 25 chromosomes studied, they found the
same haplotype (defined by 8 polymorphic restriction sites), a haplotype
seen only rarely among beta-A-bearing chromosomes. The 3 exceptions
showed identity to the typical beta-C allele in the 3-prime end of the
beta-globin gene cluster. Trabuchet et al. (1991) presented haplotyping
information suggesting a unicentric origin of the HbC mutation in
sub-Saharan Africa.

Rapid detection of the sickle cell mutation is possible by amplifying
the region of codon 6 by PCR and digesting the amplification product by
a restriction endonuclease whose recognition site is abolished by the
A-to-T mutation, the resulting abnormal fragment being detected with
ethidium bromide staining after electrophoresis. Detection of the HbC
mutation is more difficult since no known restriction-endonuclease site
is abolished or created by the mutation. Fischel-Ghodsian et al. (1990)
described a rapid allele-specific PCR amplification technique that
allowed detection of the HbC mutation in an even shorter time span than
the one required for detecting the HbS mutation (141900.0243).

To test the hypothesis that hemoglobin C protects against severe malaria
(611162), Agarwal et al. (2000) conducted a study in the predominantly
Dogon population of Bandiagara, Mali, in West Africa, where the
frequency of HbC is high (0.087) and that of HbS is low (0.016). They
found evidence for an association between HbC and protection against
severe malaria in the Dogon population. Indeed, the data suggested less
selection for the HbAS state in this group than for HbAC.

In many children with sickle cell anemia (603903), functional asplenia
develops during the first year of life and septicemia is the leading
cause of death in childhood. The risk of septicemia in sickle cell
anemia is greatest during the first 3 years of life and is reduced
markedly by prophylactic penicillin therapy. Less is known about splenic
dysfunction and the risk of overwhelming sepsis in children with SC
disease, although functional asplenia has been documented by
radionuclide liver-spleen scans in some adult patients (Ballas et al.,
1982) and an elevated erythrocyte pit count, a finding that indicates
functional asplenia in children with sickle cell anemia, also has been
found in some children with SC disease (Pearson et al., 1985). Lane et
al. (1994) reported 7 fatal cases of pneumococcal septicemia in children
with SC disease. The earliest death occurred in a 1-year-old child who
had cyanotic congenital heart; the other children were aged 3.5 to 15
years. Only 1 child had received pneumococcal vaccine or prophylactic
penicillin therapy. All 7 children had an acute febrile illness and
rapid deterioration despite parenterally administered antibiotic therapy
and intensive medical support. Erythrocyte pit counts in 2 patients were
40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings
in 5 cases included splenic congestion without infarction in 5,
splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al.
(1994) concluded that pneumococcal vaccine should be administered in all
children with SC disease. The routine use of prophylactic penicillin
therapy in infants and children with SC disease remained controversial.
The mutation in codon 6 of HBB in HbS is GAG (glu) to GTG (val); the
mutation in HbC is GAG (glu) to AAG (lys). See also 141900.0039 and
141900.0040.

Modiano et al. (2001) performed a large case-control study in Burkina
Faso on 4,348 Mossi subjects, and demonstrated that hemoglobin C is
associated with a 29% reduction in risk of clinical malaria in HbAC
heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011).
These findings, together with the limited pathology of HbAC and HbCC
compared to the severely disadvantaged HbSS and HbSC genotypes and the
low HbS gene frequency in the geographic epicenter of HbC, support the
hypothesis that, in the long-term and in the absence of malarial
control, HbC would replace HbS in central West Africa.

Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs)
from 53 families in Burkina Faso over 2 years and found that hemoglobin
C carriers were found to have less frequent malaria attacks than AA
individuals within the same age group (P = 0.01). Analysis of individual
hemoglobin alleles yielded a negative association between HbC and
malaria attack (P = 0.00013). Analyses that took into account
confounding factors confirmed the negative association of HbC with
malaria attack (P = 0.0074) and evidenced a negative correlation between
HbC and parasitemia (P = 0.0009).

Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the
cell-surface properties of P. falciparum-infected erythrocytes involved
in pathogenesis. Relative to parasite-infected normal erythrocytes
(HbAA), parasitized AC and CC erythrocytes showed reduced adhesion to
endothelial monolayers expressing CD36 (173510) and intercellular
adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting
interactions with nonparasitized erythrocytes, and reduced agglutination
in the presence of pooled sera from malaria-immune adults. Abnormal
cell-surface display of the main variable cytoadherence ligand, PfEMP-1
(P. falciparum erythrocyte membrane protein-1), correlated with these
findings. The abnormalities in PfEMP-1 display were associated with
markers of erythrocyte senescence, and were greater in CC than in AC
erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might
protect against malaria by reducing PfEMP1-mediated adherence of
parasitized erythrocytes, thereby mitigating the effects of their
sequestration in the microvasculature.

Recombinational hotspots are a ubiquitous feature of the human genome,
occurring every 60 to 200 kb, and likely contribute to the observed
pattern of large haplotypic blocks punctuated by low linkage
disequilibrium (LD) over very short (1 to 2 kb) distances. Recombination
breaks up ancestral LD and produces new combinations of alleles on which
natural selection can act. Positive selection increases the frequency of
beneficial mutations, creating LD via genetic 'hitchhiking.' The
beta-globin hotspot spans approximately 1 kb and is located
approximately 500 bp from the selected site at the beta-globin gene. The
close proximity of these beta-globin regions allowed Wood et al. (2005)
to empirically examine the signature of selection across a region that
recombines at a rate 50 to 90 times higher than the genomic average of
1.1 cM/Mb. Early studies of the HbC polymorphism suggested that this
allele was, like the hemoglobin S allele (141900.0243), also subject to
balancing selection (Allison, 1954). Subsequently, it was shown that HbC
provides protection against Plasmodium falciparum without significantly
reducing fitness, indicating that this allele is increasing in frequency
as a result of positive directional selection (Agarwal et al., 2000;
Modiano et al., 2001; Hedrick, 2004; Rihet et al., 2004). Because the
African HbC allele rarely exceeds frequencies of 20% and is
geographically concentrated in central West Africa, it is thought that
this mutation is very young. Wood et al. (2005) examined the extent of
LD surrounding the African HbC allele to estimate its age and the
strength of selection acting on this mutation and tested the hypothesis
that the beta-globin recombinational hotspot decouples the selected HbC
allele from nearby upstream regions. They estimated that the HbC
mutation originated less than 5,000 years ago and that selection
coefficients are between 0.04 and 0.09. Despite strong selection and the
recent origin of the HbC allele, recombination (crossing-over or gene
conversion) is observed within 1 kb 5-prime of the selected site on more
than one-third of the Hb chromosomes sampled. The rapid decay in LD
upstream of the HbC allele demonstrates the large effect the beta-globin
hotspot has in mitigating the effects of positive selection on linked
variation, in other words a reduction in 'hitchhiking.'

Modiano et al. (2008) adopted 2 partially independent haplotypic
approaches to study the Mossi population in Burkina Faso, where both the
HbS and HbC alleles are common. They showed that both alleles are
monophyletic, but that the HbC allele has acquired higher
recombinatorial and DNA slippage haplotypic variability or linkage
disequilibrium decay and is likely older than HbS. Modiano et al. (2008)
inferred that the HbC allele has accumulated mainly through recessive
rather than a semidominant mechanism of selection.

Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
subjects and transmission experiments involving 60 children and over
6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
variants HbC and HbS, which are protective against malaria, are
associated with transmission of the parasite from the human host to the
Anopheles mosquito vector. They found that HbC and HbS were associated
with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P
= 7.0 x 10(-5)) increases of parasite transmission from host to vector.
In addition, the HbC allele was consistently associated with higher
gametocyte rate.

Cyrklaff et al. (2011) found that HbS (141900.0243) and HbC affect the
trafficking system that directs parasite-encoded proteins to the surface
of infected erythrocytes. Cryoelectron tomography revealed that P.
falciparum generates a host-derived actin cytoskeleton within the
cytoplasm of wildtype red blood cells that connects the Maurer clefts
with the host cell membrane and to which transport vesicles are
attached. The actin cytoskeleton and the Maurer clefts were aberrant in
erythrocytes containing HbS or HbC. Hemoglobin oxidation products,
enriched in HbS and HbC erythrocytes, inhibited actin polymerization in
vitro and may account for the protective role in malaria.

.0039
HEMOGLOBIN C (GEORGETOWN)
HEMOGLOBIN C (HARLEM)
HBB, GLU6VAL AND ASP73ASN

Red cells containing this hemoglobin, with 2 mutations in the HBB gene,
sickle. The sickling is the result, of course, of the glu-to-val
mutation, which is not counteracted by the asp73-to-asn mutation. It is
called HbC (not S) because of its electrophoretic properties. See Pierce
et al. (1963), Bookchin et al. (1966, 1968, 1970), and Lang et al.
(1972).

.0040
HEMOGLOBIN C (ZIGUINCHOR)
HEMOGLOBIN ZIGUINCHOR
HBB, GLU6VAL AND PRO58ARG

As in the other cases of doubly substituted beta chains, either double
mutation or intracistronic recombination in a genetic compound would
explain the observation. This hemoglobin sickles because of its
glu6-to-val substitution, but is called HbC (not S) because of its
electrophoretic properties, which are those of classic HbC. See Goossens
et al. (1975) and Hassan et al. (1977).

.0041
HEMOGLOBIN CAMDEN
HEMOGLOBIN MOTOWN;;
HEMOGLOBIN TOKUCHI
HBB, GLN131GLU

See Cohen et al. (1973), Cotten et al. (1973), and Honig et al. (1980).
See Rucknagel (1986); hemoglobin Motown was formerly thought to be a
change at beta 127 (Gibb, 1981). See Ohba et al. (1975); hemoglobin
Tokuchi was formerly thought to be a substitution of tyrosine for
histidine at beta 2 (Shibata et al., 1963).

.0042
HEMOGLOBIN CAMPERDOWN
HBB, ARG104SER

See Wilkinson et al. (1975) and Zhao et al. (1990).

.0043
HEMOGLOBIN CARIBBEAN
HBB, LEU91ARG

See Ahern et al. (1976) and Ali et al. (1988).

.0044
HEMOGLOBIN CASTILLA
HBB, LEU32ARG

See Garel et al. (1975).

Walker et al. (2003) described heterozygosity for Hb Castilla in an
8-month-old boy with persistent hemolytic anemia.

.0045
HEMOGLOBIN CHANDIGARH
HBB, ASP94GLY

Dash et al. (1989) described Hb Chandigarh in a 35-year-old carrier of
beta-thalassemia who was the father of a child diagnosed to have
homozygous beta-thalassemia. At that time, the patient was normocytic
with normal values of hemoglobin, PCV, and RBC count. Two other
hemoglobin variants with substitutions at asp94 had been described: Hb
Barcelona (asp94 to his; 141900.0016) and Hb Bunbury (asp94 to asn;
141900.0035), both of which were described as high oxygen affinity Hb
variants, with or without erythrocytosis. Dash and Das (2004) reported
on the same patient observed 15 years later. He then had marked
hepatosplenomegaly and was found to have polycythemia. The asp94 residue
was known to form a salt bridge between its carboxyl group and the
imidazolium ion of the histidine residue at the C terminus. The loss of
this salt bridge appears to destabilize the deoxy structure and shift
the equilibrium from the deoxy to the oxy configuration.

.0046
HEMOGLOBIN CHEMILLY
HBB, ASP99VAL

See Rochette et al. (1984).

.0047
HEMOGLOBIN CHEVERLY
HBB, PHE45SER

See Yeager et al. (1983). (Hb Hammersmith is beta-42 phe to ser. Despite
the functional and structural similarities, the clinical manifestations
of Hb Cheverly are much milder than those of Hb Hammersmith.)

.0048
HEMOGLOBIN CHICO
HBB, LYS66THR

See Shih et al. (1987). Hb Chico has diminished oxygen affinity
(Bonaventura et al., 1991). Its oxygen-binding constant is about half
that of normal. Bonaventura et al. (1991) presented data on the
molecular basis of this altered property.

.0049
HEMOGLOBIN CHRISTCHURCH
HBB, PHE71SER

See Carrell (1970).

.0050
HEMOGLOBIN CITY OF HOPE
HBB, GLY69SER

See Rahbar et al. (1984) and Kutlar et al. (1989). De Angioletti et al.
(1992) detected Hb City of Hope by reversed phase high performance
liquid chromatography in an asymptomatic carrier in Naples. The
gly69-to-ser substitution, identified by fast atom bombardment mass
spectrometry, was shown to be due to a TGG-to-TGA substitution by DNA
sequencing. The mutation was associated with RFLP haplotype 9, instead
of haplotype 1, as previously reported.

.0051
HEMOGLOBIN COCHIN-PORT ROYAL
HBB, HIS146ARG

See Wajcman et al. (1975).

De Angioletti et al. (2002) described the comparable mutation in the
delta chain of hemoglobin A, designated HBA2-Monreale (142000.0038).

.0052
HEMOGLOBIN COCODY
HBB, ASP21ASN

See Boissel et al. (1981), Fabritius et al. (1985), and Ohba et al.
(1990).

.0053
HEMOGLOBIN COLLINGWOOD
HBB, VAL60ALA

See Williamson et al. (1983).

.0054
HEMOGLOBIN CONNECTICUT
HBB, ASP21GLY

See Moo-Penn (1981).

.0055
HEMOGLOBIN COVENTRY
HBB, LEU141DEL

The proband was a child who appeared to have 3 different beta chains in
addition to the delta chain of HbA2 and the gamma chain of HbF (Casey et
al., 1976, 1978). The child had Hb Sydney (beta 67 val-to-ala) and
deletion of beta 141 leu. These were in different beta genes. The
presence of 3 beta genes suggested to Lehmann (1978) that the beta
Coventry chain is in fact a beta-delta fusion chain. Fay et al. (1993)
offered the explanation of posttranslational modification of leu-141,
probably a conversion to hydroxyleucine, which was not detected by
standard amino acid analysis and sequencing methods. Of interest was the
finding that not only Hb Sydney but also another substitution at the
same codon, val67-to-gly in Hb Manukau, showed this feature. Hemoglobin
Coventry was also found in association with Hb Atlanta (leu75-to-pro)
(141900.0012).

.0056
HEMOGLOBIN COWTOWN
HBB, HIS146LEU

This variant was named for Fort Worth, Texas. Polycythemia is produced.
One member of the family was treated with P32 for presumed polycythemia
rubra vera (Schneider, 1978; Schneider et al., 1979). This and about 40
other hemoglobin variants are associated with erythrocytes. See Perutz
et al. (1984).

.0057
HEMOGLOBIN CRANSTON
HBB, 2-BP INS, CODON 144

This hemoglobin was found in an asymptomatic woman with a compensated
hemolytic state due to an unstable hemoglobin variant (Bunn et al.,
1975). The hemoglobin had an abnormally long beta chain that, starting
at amino acid 144, had the following sequence:
lys-ser-ile-thr-lys-leu-ala-phe-leu-leu-ser-asn-phe-tyr-COOH. This is
the first HbA variant known to contain isoleucine. Bunn et al. (1975)
concluded that Hb Cranston probably arose by nonhomologous crossing-over
between 2 normal beta chain genes, resulting in the insertion of 2
nucleotides (AG) at position 144, to produce a frame shift. Hb Wayne is
thought to be a frame shift mutation involving the alpha chain. Hb Tak
is another hemoglobin with abnormally long beta chain. Hb Constant
Spring, Hb Koya Dora, and Hb Icaria are hemoglobins with abnormally long
alpha chains. See Shaeffer et al. (1980).

.0058
HEMOGLOBIN CRETE
HBB, ALA129PRO

See Maniatis et al. (1979).

Christopoulou et al. (2004) identified a 1368G-C transversion in exon 3
of the beta-globin gene, resulting in an ala129-to-pro (A129P)
substitution. Both the proband and her mother, who were found to be
heterozygous for Hb Crete, presented with mild microcytic anemia and
normal hemoglobin A2 levels and iron metabolism indices.

.0059
HEMOGLOBIN CRETEIL
HBB, SER89ASN

Erythrocytosis results. See Thillet et al. (1976) and Poyart et al.
(1978).

.0060
HEMOGLOBIN D (BUSHMAN)
HBB, GLY16ARG

See Wade et al. (1967).

.0061
HEMOGLOBIN D (GRANADA)
HBB, GLU22VAL

See de Pablos et al. (1987).

.0062
HEMOGLOBIN D (IBADAN)
HBB, THR87LYS

See Watson-Williams et al. (1965).

.0063
HEMOGLOBIN D (IRAN)
HBB, GLU22GLN

See Rohe et al. (1972), Rahbar (1973), and Serjeant et al. (1982).

.0064
HEMOGLOBIN D (OULED RABAH)
HBB, ASN19LYS

See Elion et al. (1973) and Ren et al. (1988).

Among 598 children from the Berber population of the Mzab, Merghoub et
al. (1997) found HbC and Hb D (Ouled Rabah) in the same gene frequency
(0.015). Hb D(Ouled Rabah) is considered a private marker of the Kel
Kummer Tuaregs. Haplotype analysis suggested a single origin of the Hb D
mutation. Genetic markers calculated from blood group data clustered
Mozabites and Tuaregs with the other Berber-speaking groups,
Arabic-speaking populations being more distant. However, they found no
specific relationship between the Mozabites and Kel Kummers. Tuaregs in
general exhibit features that tend to differentiate them from other
Berber-speaking groups. Merghoub et al. (1997) concluded that Hb D(Ouled
Rabah) may be specific for Berber-speaking populations. Merghoub et al.
(1997) noted that the origin of the Berber people is not clearly
established. North Africa was peopled around the sixteenth millennium
B.C.; transition to agriculture occurred around 9500 to 7000 B.C.,
spreading from the Near East to Egypt. The Arab invasion in the seventh
and eighth centuries brought Islamization and dispersal of the Berber
culture. Present-day populations of North Africa are mostly
Arabic-speaking, whatever their remote origin. Berbers, however, with
their languages and customs, still live in small niches of northern
Morocco and Algeria, and in some northern oases of the Sahara, including
those of the Mzab (Algeria). The Tuaregs also speak Berber languages.
They inhabit the south of the Sahara and have been involved for
centuries in trans-Saharan trade. Tuaregs have their own culture that
probably diverged from the Berber world through isolation.

.0065
HEMOGLOBIN D (PUNJAB)
HEMOGLOBIN D (CHICAGO);;
HEMOGLOBIN D (LOS ANGELES);;
HEMOGLOBIN D (NORTH CAROLINA);;
HEMOGLOBIN D (PORTUGAL);;
HEMOGLOBIN OAK RIDGE
HBB, GLU121GLN

See Benzer et al. (1958), Bowman and Ingram (1961), Stout et al. (1964),
Schneider et al. (1968), Lehmann and Carrell (1969), Ozsoylu (1970),
Imamura and Riggs (1972), Bunn et al. (1978), Trent et al. (1982),
Worthington and Lehmann (1985), Husquinet et al. (1986), and Harano et
al. (1987). Hemoglobin D (Punjab) is common worldwide. It is the most
frequent abnormal hemoglobin in Xinjiang Uygur Autonomous Region of
China (Li et al., 1986). Zeng et al. (1989) used the PCR method for
population studies of this variant. Using PCR and direct sequencing,
Schnee et al. (1990) demonstrated the predicted G-to-C substitution in
codon 121.

.0066
HEMOGLOBIN DEER LODGE
HBB, HIS2ARG

See Labossiere et al. (1972), Powars et al. (1977), and Shulman and Bunn
(1988).

.0067
HEMOGLOBIN DETROIT
HBB, LYS95ASN

See Moo-Penn et al. (1978).

.0068
HEMOGLOBIN DJELFA
HBB, VAL98ALA

See Gacon et al. (1977).

.0069
HEMOGLOBIN DOHA
HBB, NH2 EXTENSION, VAL1GLU

Kamel et al. (1985) investigated a Qatari family with an
electrophoretically fast-moving hemoglobin that they found contained an
abnormal beta chain with the sequence met-glu-his-leu at the NH2-end.
Substitution of glutamic acid for valine at beta 1 apparently prevented
removal of the initiator methionine. The methionine was blocked by a
molecule not completely identified. No clinical consequences were
observed in heterozygotes.

.0070
HEMOGLOBIN DUARTE
HBB, ALA62PRO

See Beutler et al. (1974).

.0071
HEMOGLOBIN E
BETA-PLUS-THALASSEMIA;;
BETA-E-THALASSEMIA;;
MALARIA, RESISTANCE TO, INCLUDED
HBB, GLU26LYS

This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and
Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks
et al. (1980), Benz et al. (1981), and Kazazian et al. (1984).

Orkin et al. (1982) reported the complete nucleotide sequence of a
beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the
only abnormality. Expression of the beta-E gene was tested by
introducing it into HeLa cells. Two abnormalities of RNA processing were
shown: slow excision of intervening sequence-1 and alternative splicing
into exon 1 at a cryptic donor sequence within which the codon 26
nucleotide substitution resides.

Antonarakis et al. (1982) used the Kazazian haplotype approach of
analyzing DNA polymorphisms in the beta-globin cluster to present
evidence that the beta-E mutation occurred at least twice in Southeast
Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could
be recognized by the restriction enzyme MnlI which cleaves DNA at the
sequence 3-prime-GGAG-5-prime.

Rey et al. (1991) described SE disease in 3 black American children of
Haitian origin. They pointed out that the disorder is probably more
benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of
which have increased risk of the complications of sickling including
pneumococcal sepsis.

Rees et al. (1996) reported a girl homozygous for Hb E with severe
anemia and anisopoikilocytosis, who was also homozygous for pyrimidine
5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient
for P5N, the stability of the Hb E was decreased.

Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et
al. (2002) examined the possible protective role of Hb E and other
prevalent inherited hemoglobin abnormalities against malaria (611162) in
Thailand. They assessed the effect of Hb E by means of a mixed
erythrocyte invasion assay. In vitro, starting at 1% parasitemia,
Plasmodium falciparum preferentially invaded normal (HbAA) compared to
abnormal hemoglobin red blood cells, including those heterozygous and
homozygous for Hb E. The heterozygote HbAE cells differed markedly from
all the other cells tested, with invasion restricted to approximately
25% of the red blood cells. Despite their microcytosis, AE heterozygous
cells were functionally relatively normal in contrast to the red blood
cells from the other hemoglobinopathies studied. Chotivanich et al.
(2002) interpreted these findings as suggesting that HbAE erythrocytes
have an unidentified membrane abnormality that renders most of the red
blood cell population relatively resistant to invasion by P. falciparum.
This would not protect from uncomplicated malaria infections but would
prevent the development of heavy parasite burdens and was considered
consistent with the 'Haldane hypothesis' of heterozygote protection
against severe malaria for Hb E.

The Hb E variant is concentrated in parts of Southeast Asia where
malaria is endemic, and Hb E carrier status confers some protection
against Plasmodium falciparum malaria. To examine the effect of natural
selection on the pattern of linkage disequilibrium (LD) and to infer the
evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed
biallelic markers surrounding the Hb E variant in a Thai population.
Pairwise LD analysis of Hb E and 43 surrounding biallelic markers
revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed
between non-Hb E variants and the same markers. The inferred haplotype
network suggested a single origin of the Hb E variant in the Thai
population. Forward-in-time computer simulations under a variety of
selection models indicated that the Hb E variant arose 1,240 to 4,440
years ago. Thus, the Hb E mutation occurred recently and allele
frequency increased rapidly. The study demonstrated that a high
resolution LD map across the human genome can detect recent variants
that have been subjected to positive selection.

The highest frequencies of the Hb E gene in large population samples,
approximately 0.3, had been observed in the southern part of
northeastern Thailand. Even higher frequencies were observed by Flatz et
al. (2004) in Austroasiatic populations in southern Laos. One frequency
was as high as 0.433 in a population of Sekong Province.

As in other areas of Southeast Asia, hemoglobin E is a very common
hemoglobin variant in India, where the highest prevalence of hemoglobin
E has been observed in the northeastern regions. In West Bengal, carrier
frequency varies from 5 to 35% in different subpopulations, whereas in
Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%.
Individuals heterozygous for hemoglobin E have normal or near-normal
mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in
peripheral blood. Homozygosity for hemoglobin E is commonly benign,
characterized by mild hypochromic microcytic anemia with the presence of
target cells. Edison et al. (2005) observed hyperbilirubinemia among
patients with homozygosity for the hemoglobin E gene in the Indian
population, with jaundice being the major complaint at presentation. A
study of UGT1A1 gene polymorphism showed that the variant TA(7) in the
promoter region of the UGT1A1 gene (191740.0011) was associated with
hyperbilirubinemia in homozygous HbE patients.

The role of the TA(7) polymorphism of UGT1A1 in the determination of
jaundice and gallstones in hemoglobin E beta-thalassemia had been
pointed out by Premawardhena et al. (2001) in studies from Sri Lanka.
The same group (Premawardhena et al., 2003) studied the global
distribution of length polymorphisms of the promoters of the UGT1A1
gene. They found that homozygosity for the TA(7) allele occurred in 10
to 25% of the populations of Africa and the Indian subcontinent, with a
variable frequency in Europe. It occurred at a much lower frequency in
Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to
5%. African populations showed a much greater diversity of length
alleles than other populations. These findings defined those populations
with a high frequency of hemoglobin E beta-thalassemia and related
disorders that are at increased risk for hyperbilirubinemia and gall
bladder disease. Beutler et al. (1998) had suggested that the wide
diversity in the frequency of the UGT1A1 promoter alleles might reflect
a balanced polymorphism mediated through the protective effect of
bilirubin against oxidative damage.

O'Donnell et al. (2009) studied Sri Lankan patients with HbE
beta-thalassemia for exposure to malaria caused by P. falciparum or P.
vivax. They found that there were high frequencies of antibodies to both
malaria parasites, as well as DNA-based evidence of current infection
with P. vivax. Comparisons with age-matched controls showed that there
was a higher frequency of antibodies in thalassemic patients,
particularly against P. vivax and in young children, that was unlikely
to be related to transfusion. A higher frequency was also found in
patients who had undergone splenectomy. O'Donnell et al. (2009) proposed
that patients with HbE beta-thalassemia may be more prone to malaria,
particularly P. vivax malaria.

The estimated number of worldwide annual births of patients with HbE
beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall,
2010).

.0072
HEMOGLOBIN E (SASKATOON)
HBB, GLU22LYS

See Vella et al. (1967) and Gonzalez-Redondo et al. (1987). Gurgey et
al. (1990) found compound heterozygosity for this mutation and
beta-thalassemia of type IVS1-6 (141900.0360). Igarashi et al. (1995)
identified Hb E-Saskatoon in a Japanese male. Igarashi et al. (1995)
reported what they stated was the first case of Hb-E (Saskatoon) in a
Japanese male.

Birben et al. (2001) described Hb E-Saskatoon in homozygous state in a
30-year-old Turkish woman. The consanguineous parents were heterozygotes
for the abnormal hemoglobin. The heterozygous son of the proband had
mild anemia; physical examination of the child and family members
revealed no abnormalities. The parameters of routine hematologic studies
were within normal limits.

.0073
HEMOGLOBIN EDMONTON
HBB, THR50LYS

See Labossiere et al. (1971). Landin et al. (1996) pointed out that 2
nucleotide substitutions in codon 50, either ACT to AAA, or ACT to AAG,
would be required to produce this amino acid substitution. The same is
true for the amino acid substitutions in Hb Bristol (141900.0030) and Hb
Beckman (141900.0442) among the beta-globin variants and Hb J-Kurosh
(141800.0066), an alpha-globin variant.

.0074
HEMOGLOBIN EXTREMADURA
HBB, VAL133LEU

In a Spanish female with mild hemolytic anemia, Villegas et al. (1989)
demonstrated this mildly unstable hemoglobin.

.0075
HEMOGLOBIN FANNIN-LUBBOCK
HBB, VAL111LEU AND GLY119ASP

See Moo-Penn et al. (1976). In 5 apparently, unrelated Spanish adults,
Qin et al. (1994) found a fast-moving hemoglobin variant and observed a
GGC-to-GAC mutation at codon 119 which had previously been identified as
the abnormality in Hb Fannin-Lubbock. In addition, however, they found a
GTC-to-CTC change at codon 111 which led to a val-to-leu substitution.
Protein analysis in one of the individuals confirmed that the 2
mutations were located on the same chromosome. Qin et al. (1994)
suggested that some other known variants may carry an additional
mutation that results in an electrophoretically silent amino acid
substitution which may, however, have an effect on the physicochemical
properties of the protein. In the case of Hb Fannin-Lubbock, it appeared
likely that the val111-to-leu substitution, rather than the
gly119-to-asp replacement, was the cause of the instability of the
variant. The Hb Fannin-Lubbock variant in these Spanish families had a
normal oxygen affinity.

.0076
HEMOGLOBIN FREIBURG
HEMOGLOBIN M (FREIBURG)
HBB, VAL23DEL

Deletion of val23 from otherwise normal beta chain probably occurred
through triplet deletion resulting from unequal crossing-over between 2
normal beta loci in 1 parent of the proband. Two of 3 living children of
the proband also had the abnormal hemoglobin, which was accompanied by
slight cyanosis in all 3 and by a hemolytic process in the proband. See
Jones et al. (1966) and Horst et al. (1988).

.0077
HEMOGLOBIN FUKUOKA
HBB, HIS2TYR

See Harano et al. (1990).

.0078
HEMOGLOBIN FUKUYAMA
HBB, HIS77TYR

See Hidaka et al. (1988).

.0079
HEMOGLOBIN G (ACCRA)
HBB, ASP79ASN

There is no clinical or hematologic abnormality in the homozygote. See
Edington et al. (1955), Gammack et al. (1961), Lehmann et al. (1964),
and Milner (1967).

.0080
HEMOGLOBIN G (COPENHAGEN)
HBB, ASP47ASN

See Sick et al. (1967), Schiliro et al. (1981), and Chen et al. (1985).

.0081
HEMOGLOBIN G (COUSHATTA)
HEMOGLOBIN G (SASKATOON);;
HEMOGLOBIN G (HSIN-CHU);;
HEMOGLOBIN G (TAEGU)
HBB, GLU22ALA

See Schneider et al. (1964), Bowman et al. (1967), Vella et al. (1967),
Blackwell et al. (1967), Blackwell et al. (1968), Blackwell et al.
(1969), Ohba et al. (1978), Niazi et al. (1981), and Dincol et al.
(1989).

.0082
HEMOGLOBIN G (FERRARA)
HBB, ASN57LYS

See Giardina et al. (1978).

.0083
HEMOGLOBIN G (GALVESTON)
HEMOGLOBIN G (PORT ARTHUR);;
HEMOGLOBIN G (TEXAS)
HBB, GLU43ALA

See Bowman et al. (1962, 1964).

.0084
HEMOGLOBIN G (HSI-TSOU)
HBB, ASP79GLY

See Blackwell et al. (1972).

.0085
HEMOGLOBIN G (MAKASSAR)
HBB, GLU6ALA

See Blackwell et al. (1970).

.0086
HEMOGLOBIN G (SAN JOSE)
HBB, GLU7GLY

This hemoglobin oxy was first described in a family of Calabrian origin
by Schwartz et al. (1957). The molecular defect was demonstrated by Hill
et al. (1960). Brancati et al. (1989) reported a case of homozygosity in
a healthy male with normal hematologic findings. See Hill and Schwartz
(1959), Ricco et al. (1974), Wilson et al. (1980), and Schiliro et al.
(1981).

.0087
HEMOGLOBIN G (SZUHU)
HEMOGLOBIN GIFU
HBB, ASN80LYS

See Blackwell et al. (1969), Imai et al. (1970), Kaufman et al. (1975),
Welch (1975) and Romero et al. (1985). Schiliro et al. (1991) found this
abnormal hemoglobin in 4 members from 2 generations of a Sicilian
family.

.0088
HEMOGLOBIN G (TAIPEI)
HBB, GLU22GLY

See Blackwell et al. (1969), Zeng et al. (1981), and Landman et al.
(1987).

.0089
HEMOGLOBIN G (TAIWAN-AMI)
HBB, GLY25ARG

See Blackwell and Liu (1968).

.0090
HEMOGLOBIN GAINESVILLE-GA
HBB, GLY46ARG

See Chen et al. (1985).

.0091
HEMOGLOBIN GAVELLO
HBB, ASP47GLY

See Marinucci et al. (1977).

.0092
HEMOGLOBIN GEELONG
HEMOGLOBIN JINAN
HBB, ASN139ASP

See Como et al. (1984).

.0093
HEMOGLOBIN GENOVA
HEMOGLOBIN HYOGO
HBB, LEU28PRO

Unstable hemoglobin. See Sansone et al. (1967), Labie et al. (1972),
Kendall et al. (1979), Shibata et al. (1980), and Hopmeier et al.
(1990).

.0094
HEMOGLOBIN GRANGE-BLANCHE
HBB, ALA27VAL

See Baklouti et al. (1987).

.0095
HEMOGLOBIN GUN HILL
HBB, 15-BP DEL

Deletion of amino acid residues 93-97 inclusive of beta chain probably
through unequal crossing over. This unstable hemoglobin also has absence
of half of the normal complement of heme. Other unstable hemoglobins
include Hb Zurich, Hb Koln, Hb Geneva, Hb Sydney, Hb Hammersmith and Hb
Sinai. (It is possible that the deletion is 91-95 or 92-96 rather than
93-97.) See Bradley et al. (1967) and Rieder and Bradley (1968). See Hb
Koriyama (141900.0152).

.0096
HEMOGLOBIN HACETTEPE
HEMOGLOBIN COMPLUTENSE
HBB, GLN127GLU

See Altay et al. (1976) and Huisman et al. (1986).

.0097
HEMOGLOBIN HAFNIA
HBB, HIS116GLN

By isoelectric focusing (IEF) of red cell hemolysates, this hemoglobin
variant simulates glycated hemoglobin (HbA1c). This is the first
mutation discovered at beta 116. It was first found in a 6-year-old boy
with diabetes mellitus; 5 nondiabetic members of the family had the same
hemoglobin variant (Blanke et al., 1988). (Hafnia is Latin for
Copenhagen.)

During neonatal screening in Belgium, Cotton et al. (2000) found a
newborn of Brazilian origin with Hb Hafnia. Both he and his mother were
heterozygous for a CAT-to-CAA transversion at codon 116. Both were
clinically and hematologically normal.

.0098
HEMOGLOBIN HAMADAN
HBB, GLY56ARG

See Rahbar et al. (1975).

Akar et al. (2003) described the first observation of homozygous Hb
Hamadan in a Turkish family. In this family 1 member was a compound
heterozygote for Hb Hamadan and beta-thalassemia due to a -29A-G
promoter mutation (141900.0379). Neither homozygous Hb Hamadan nor a
combination with beta-thalassemia appeared to have clinical
significance.

.0099
HEMOGLOBIN HAMILTON
HBB, VAL11ILE

See Manca et al. (1987) and Wong et al. (1984). Manca et al. (1992)
described an easy PCR-based method for demonstration of the mutation.
They demonstrated the predicted G-to-A transition at codon 11 which
abolishes a MaeIII restriction site. This mutation, which is rather
common among Sardinians, involves one of the 5 CpG dinucleotides of the
beta-globin gene.

.0100
HEMOGLOBIN HAMMERSMITH
HEMOGLOBIN CHIBA;;
HEINZ BODY HEMOLYTIC ANEMIA
HBB, PHE42SER

The normal phenylalanine at this site apparently 'stabilizes' the heme
with which it is in contact. The substitution of serine leads to severe
Heinz body hemolytic anemia. See Dacie et al. (1967), Ohba et al.
(1975), and Rahbar et al. (1981). Dianzani et al. (1991) demonstrated a
de novo phe42-to-ser mutation using the chemical cleavage of mismatch
method (CCM) of Cotton et al. (1988). The responsible substitution was a
TTT-to-TCT change. The report of rare cases of this hemoglobinopathy in
different ethnic groups also supports the occurrence of independent
mutations.

.0101
HEMOGLOBIN HAZEBROUCK
HBB, THR38PRO

See Blouquit et al. (1985).

.0102
HEMOGLOBIN HEATHROW
HBB, PHE103LEU

Hb Heathrow is a cause of erythrocytosis because of increase in oxygen
affinity. The mutation occurs in the same codon as that in Hb Saint
Nazaire (141900.0436).

See White et al. (1973).

.0103
HEMOGLOBIN HELSINKI
HBB, LYS82MET

This is a cause of familial erythrocytosis. See Ikkala et al. (1976).

.0104
HEMOGLOBIN HENRI MONDOR
HBB, GLU26VAL

See Blouquit et al. (1976) and Bardakdjian et al. (1987).

.0105
HEMOGLOBIN HIJIYAMA
HBB, LYS120GLU

See Miyaji et al. (1968).

.0106
HEMOGLOBIN HIKARI
HBB, LYS61ASN

Heterozygotes have about 60% hemoglobin Hikari. See Shibata and Iuchi
(1962) and Shibata et al. (1964).

.0107
HEMOGLOBIN HIMEJI
HBB, ALA140ASP

This hemoglobin was found in a diabetic because its N-terminal glycation
was about 3 times that of the normal (Ohba et al., 1986).

.0108
HEMOGLOBIN HINSDALE
HBB, ASN139LYS

See Moo-Penn et al. (1989).

.0109
HEMOGLOBIN HIROSE
HBB, TRP37SER

See Yanase et al. (1968) and Ohba et al. (1983).

.0110
HEMOGLOBIN HIROSHIMA
HBB, HIS146ASP

Associated with increased oxygen affinity, decreased Bohr effect, and
erythremia. (The substitution was formerly thought to be at residue
143.) See Hamilton et al. (1969) and Perutz et al. (1971).

.0111
HEMOGLOBIN HOFU
HBB, VAL126GLU

See Miyaji et al. (1968), Brittenham et al. (1978), Ohba et al. (1981),
and Arends et al. (1985).

.0112
HEMOGLOBIN HOPE
HBB, GLY136ASP

See Minnich et al. (1965), Steinberg et al. (1974, 1976), Charache et
al. (1979), Harano et al. (1983), Martinez and Colombo (1984), and Enoki
et al. (1989). In a Thai Mien family, Pillers et al. (1992) observed Hb
Hope in compound heterozygous state with Hb E. Previous reports of Hb
Hope had involved predominantly black Americans, blacks who lived in
Cuba, or natives of Mali who lived in France.

Ingle et al. (2004) analyzed interactions of Hb Hope with Hb S
(141900.0243), other variant hemoglobins, and thalassemia.

.0113
HEMOGLOBIN HOSHIDA
HEMOGLOBIN CHAYA
HBB, GLU43GLN

See Iuchi et al. (1978) and Shibata et al. (1980). Plaseska et al.
(1991) observed this mutation, due to a GAG-to-CAG change at codon 43,
in a Yugoslavian family.

.0114
HEMOGLOBIN HOTEL-DIEU
HBB, ASP99GLY

See Blouquit et al. (1981).

.0115
HEMOGLOBIN I (HIGH WYCOMBE)
HBB, LYS59GLU

See Boulton et al. (1970), Lacombe et al. (1987), and Wilkinson et al.
(1987).

Hamaguchi et al. (2000) reported the first case of hemoglobin I (High
Wycombe) in Japan. It was suspected because of a discrepancy between
blood glucose status and glycated hemoglobin measurements in a
55-year-old diabetic female.

.0116
HEMOGLOBIN I (TOULOUSE)
HEMOGLOBIN TOULOUSE
HBB, LYS66GLU

See Rosa et al. (1969) and Labie et al. (1971).

.0117
HEMOGLOBIN INDIANAPOLIS
HEINZ BODY HEMOLYTIC ANEMIA
HBB, CYS112ARG

Adams et al. (1978, 1979) studied father and daughter with a clinical
picture of beta-thalassemia which was due to labile beta-chains
resulting in Heinz body formation in normoblasts. The changes in the
beta-chains were posttranslational. Baiget et al. (1986) and De Biasi et
al. (1988) described 2 new families with the cys112-to-arg mutation. In
these families the carriers were not anemic, had normal chromic and
normocytic red cells, and displayed only mild reticulocytosis. This
prompted Coleman et al. (1991) to restudy the original family with the
finding that the mutation in fact was leu106-to-arg. In order to avoid
confusion, they renamed the original mutation Hb Terre Haute (see
141900.0398).

.0118
HEMOGLOBIN ISTANBUL
HEMOGLOBIN SAINT ETIENNE
HBB, HIS92GLN

One patient had an apparent new mutation; the father was 41 years old
and the mother 36 at the patient's birth (Aksoy et al. (1972)). See
Beuzard et al. (1972) and Aksoy and Erdem (1979).

De Weinstein et al. (2000) described this hemoglobin variant in a
36-year-old Argentinian female of Spanish-Portuguese origin. She
presented with chronic hemolytic anemia, jaundice, splenomegaly, and
gallstones from childhood. She required blood transfusion during her
only pregnancy at the age of 23. She underwent splenectomy and
cholecystectomy when she was 33 years old. Her 13-year-old son also
presented with chronic hemolytic anemia, jaundice, and splenomegaly. It
was the third observation of this hemoglobin variant. In the first 2
cases, origination was by de novo mutation. This was the first case in
which the precise DNA change was identified: codon 92 was changed from
CAC (his) to CAG (gln).

.0119
HEMOGLOBIN J (ALTGELD GARDENS)
HBB, HIS92ASP

See Adams et al. (1975, 1978).

.0120
HEMOGLOBIN J (AMIENS)
HBB, LYS17ASN

See Elion et al. (1979) and Harano et al. (1990).

.0121
HEMOGLOBIN J (ANTAKYA)
HBB, LYS65MET

See Huisman et al. (1986).

.0122
HEMOGLOBIN J (AUCKLAND)
HBB, GLY25ASP

See Williamson et al. (1987).

.0123
HEMOGLOBIN J (BALTIMORE)
HEMOGLOBIN J (IRELAND);;
HEMOGLOBIN J (TRINIDAD);;
HEMOGLOBIN J (GEORGIA);;
HEMOGLOBIN N (NEW HAVEN 2)
HBB, GLY16ASP

Fast hemoglobin. See Went and MacIver (1959), Gammack et al. (1961),
Sydenstricker et al. (1961), Huisman and Sydenstricker (1962),
Weatherall (1964), Chernoff and Perillie (1964), Wilkinson et al.
(1967), Wong et al. (1971), and Musumeci et al. (1979).

.0124
HEMOGLOBIN J (BANGKOK)
HEMOGLOBIN J (KORAT);;
HEMOGLOBIN J (MANADO);;
HEMOGLOBIN J (MEINUNG)
HBB, GLY56ASP

See Clegg et al. (1966), Blackwell and Liu (1966), Pootrakul et al.
(1967), Blackwell et al. (1970), and Iuchi et al. (1981).

.0125
HEMOGLOBIN J (CAIRO)
HBB, LYS65GLN

See Garel et al. (1976).

.0126
HEMOGLOBIN J (CALABRIA)
HEMOGLOBIN J (COSENZA);;
HEMOGLOBIN J (BARI)
HBB, GLY64ASP

See Tentori (1974) and Marinucci et al. (1979).

.0127
HEMOGLOBIN J (CHICAGO)
HBB, ALA76ASP

See Romain et al. (1975). This hemoglobin was discovered in a 2-year-old
black child from Chicago, who was hospitalized for iron deficiency
anemia. The second case was reported in a Spanish family by Arrizabalaga
et al. (1998).

.0128
HEMOGLOBIN J (CORDOBA)
HBB, LYS95MET

See Bardakdjian et al. (1988).

.0129
HEMOGLOBIN J (DALOA)
HBB, ASN57ASP

See Boissel et al. (1982).

.0130
HEMOGLOBIN J (GUANTANAMO)
HBB, ALA128ASP

The first reported cases were in a Cuban family of African ancestry
(Martinez et al., 1977). Wajcman et al. (1988) described a case from
Benin in Nigeria. Also see Zhu et al. (1988) and Sciarratta et al.
(1990). Yamagishi et al. (1993) identified this mutation in a Japanese
family during assay of glycated hemoglobins by ion exchange high
performance liquid chromatography. No anemia or hemolysis was observed
in the affected members of the family, although one member had a
decreased haptoglobin value.

.0131
HEMOGLOBIN J (IRAN)
HBB, HIS77ASP

See Gammack et al. (1961), Rahbar et al. (1967), and Delanoe-Garin et
al. (1986). Bircan et al. (1990) observed compound heterozygosity of
this variant with Hb N (Baltimore) (141900.0188).

.0132
HEMOGLOBIN J (KAOHSIUNG)
HEMOGLOBIN J (HONOLULU)
HBB, LYS59THR

See Blackwell et al. (1971) and Blackwell et al. (1972). Chang et al.
(1992) described a new RFLP created by this substitution.

.0133
HEMOGLOBIN J (LENS)
HBB, ALA13ASP

See Djoumessi et al. (1981).

.0134
HEMOGLOBIN J (LOME)
HBB, LYS59ASN

See Wajcman et al. (1977) and Prior et al. (1989).

.0135
HEMOGLOBIN J (LUHE)
HBB, LYS8GLN

See Lin et al. (1992).

.0136
HEMOGLOBIN J (RAMBAM)
HEMOGLOBIN J (CAMBRIDGE)
HBB, GLY69ASP

See Salomon et al. (1965) and Sick et al. (1967).

Plaseska-Karanfilska et al. (2000) described Hb Rambam in a family in
Argentina. It was combined in compound heterozygous state with a form of
beta-zero-thalassemia due to deletion of 2 nucleotides (CT) from codon
5. The latter mutation had been found among Bulgarian, Turkish, Greek,
Macedonian, North African, and Middle Eastern populations, and in some
populations of the Indian subcontinent.

.0137
HEMOGLOBIN J (SICILIA)
HBB, LYS65ASN

See Ricco et al. (1974).

.0138
HEMOGLOBIN J (TAICHUNG)
HBB, ALA129ASP

See Blackwell et al. (1969).

.0139
HEMOGLOBIN JIANGHUA
HBB, LYS120ILE

See Lu et al. (1983).

.0140
HEMOGLOBIN JOHNSTOWN
HBB, VAL109LEU

See Jones et al. (1990).

Hb Johnstown, caused by a change of codon 109 in exon 3 of the HBB gene
from GTG (val) to CTG (leu) (val109 to leu), is a high oxygen affinity
hemoglobin variant. Feliu-Torres et al. (2004) identified Hb Johnstown
in association with beta-zero-thalassemia of the IVS1AS-1G-A
(141900.0356) type in an 8-year-old girl referred because of
erythrocytosis and a left-shifted oxygen dissociation curve. The mother
was found to be heterozygous for the Hb variant and the father was a
beta-zero-thalassemia carrier. This Hb variant had normal
electrophoresis. The erythrocytosis and low values for actual P50 due to
Hb Johnstown were more marked due to the coinheritance of the
beta-zero-thalassemia.

.0141
HEMOGLOBIN K (CAMEROON)
HBB, ALA129GLU OR ALA129ASP

See Allan et al. (1965).

.0142
HEMOGLOBIN K (IBADAN)
HBB, GLY46GLU

See Allan et al. (1965). Castagnola et al. (1990) found this variant in
an Italian family.

.0143
HEMOGLOBIN K (WOOLWICH)
HBB, LYS132GLN

See Allan et al. (1965) and Ringelhann et al. (1971).

.0144
HEMOGLOBIN KAIROUAN
HEMOGLOBIN MONROE
HBB, ARG30THR

Codon 30 (for arginine) is interrupted between the second and third
nucleotide by the first intervening sequences of 130 nucleotides.
Modifications of the consensus sequence of the donor-splice site of IVS1
will affect the process of splicing. In hemoglobin Monroe, the G-to-C
mutation occurred at a nucleotide position adjacent to the GT
dinucleotide required for splicing; this substitution would be expected
to cause greatly decreased splicing and severe beta-plus-thalassemia, as
was observed in the family reported by Gonzalez-Redondo et al. (1989).
In a Mediterranean type of beta-plus-thalassemia, Vidaud et al. (1989)
found a G-to-C transversion in codon 30 that altered both beta-globin
pre-mRNA splicing and the structure of the hemoglobin product.
Presumably, this G-to-C transversion at position -1 of intron 1 reduced
severely the utilization of the normal 5-prime splice site, since the
level of the arg-to-thr mutant hemoglobin (designated hemoglobin
Kairouan) was very low in heterozygotes (2% of total hemoglobin). Since
no natural mutations of the guanine located at position -1 of the
CAG/GTAAGT consensus sequence had been isolated previously, Vidaud et
al. (1989) studied the role of this nucleotide in cell-free extracts.
They found that correct splicing was 98% inhibited. Thus, the last
residue of exon 1 plays a role at least equivalent to that of the intron
residue at position 5.

.0145
HEMOGLOBIN KANSAS
HEMOGLOBIN REISSMANN ET AL.
HBB, ASN102THR

This hemoglobin variant has a low oxygen affinity, resulting in
cyanosis. See Reissmann et al. (1961) and Bonaventura and Riggs (1968).

.0146
HEMOGLOBIN KEMPSEY
HBB, ASP99ASN

See Reed et al. (1968).

.0147
HEMOGLOBIN KENITRA
HBB, GLY69ARG

See Delanoe-Garin et al. (1985).

.0148
HEMOGLOBIN KHARTOUM
HBB, PRO124ARG

See Clegg et al. (1969).

.0149
HEMOGLOBIN KNOSSOS
BETA-PLUS-THALASSEMIA;;
BETA-KNOSSOS-THALASSEMIA
HBB, ALA27SER

See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al.
(1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin
Knossos is a cause of beta-thalassemia (613985), as is hemoglobin E.
Orkin et al. (1984) isolated the beta(Knossos) gene and examined its
expression in HeLa cells. Using a cryptic splice sequence that is
enhanced by the Knossos substitution, they found that some beta(Knossos)
transcripts were abnormally processed. In addition to Hb E, a silent
substitution at beta 24 causes thalassemia by abnormal RNA processing.

.0150
HEMOGLOBIN KOFU
HBB, THR84ILE

See Harano et al. (1986).

.0151
HEMOGLOBIN KOLN
HEMOGLOBIN UBE-1;;
HEMOGLOBIN SAN FRANCISCO (PACIFIC);;
HEINZ BODY HEMOLYTIC ANEMIA
HBB, VAL98MET

See Shibata et al. (1961), Pribilla (1962), Hutchison et al. (1964),
Pribilla et al. (1965), Carrell et al. (1966), Jackson et al. (1967),
Jones et al. (1967), Woodson et al. (1970), Miller et al. (1971),
Lie-Injo et al. (1972), and Ohba et al. (1973). Bradley et al. (1980)
described a convincing instance of gonadal mosaicism accounting for an
unusual pedigree pattern in a family with Hb Koln. Normal parents had 2
affected children and each of these 2 children had an affected child.
This is the most common form of unstable hemoglobin. Horst et al. (1986)
prepared DNA of 19 nucleotides, corresponding in length to the normal
and mutant gene sequences, and demonstrated its use for the direct assay
of the beta-Koln gene. The use of synthetic oligonucleotides established
that the Hb Koln mutation is due to a G-to-A transition.

Landin et al. (1994) found Hb Koln as a new mutation in 3 independent
cases of chronic hemolytic anemia in Sweden. The 2 children and 1 adult
had partially compensated hemolysis and presented with aggravated
hemolysis during acute infections in childhood. In 1 patient, acute B19
parvovirus infection induced an aplastic crisis. Diagnosis was based on
hemoglobin instability testing and isoelectric focusing of hemoglobin
dimers. Landin et al. (1994) demonstrated that PCR-RFLP can be used in
diagnosis.

Chang et al. (1998) reported the first case of Hb Koln in the Chinese
population.

.0152
HEMOGLOBIN KORIYAMA
HBB, 15-BP INS

See Kawata et al. (1988). Whereas 5 amino acid residues are deleted in
Hb Gun Hill (141900.0095), 5 amino acid residues are inserted at the
corresponding site in Hb Koriyama.

.0153
HEMOGLOBIN KORLE-BU
HBB, ASP73ASN

Since this same substitution is present with the sickle hemoglobin
change as one of the two defects in hemoglobin C(Harlem), Konotey-Ahulu
et al. (1968) suggested that the latter hemoglobin may have arisen by
intracistronic crossing-over in an individual with the Korle-Bu gene on
one chromosome and the sickle gene on the other. See Konotey-Ahulu et
al. (1968) and Honig et al. (1983). Nagel et al. (1993) showed that
compound heterozygosity for hemoglobin Korle-Bu (HbKB) and HbC
(141900.0038) is associated with moderate chronic hemolytic anemia with
microcytosis. They found that in vitro hemoglobin crystals formed within
2 minutes compared with 30 minutes for a mixture of 40% HbC and 60% HbS
and within 180 minutes for 40% HbC with 60% HbA. The crystals were cubic
in contrast with the tetragonal crystals observed in CC and SC disease.
They concluded that the hemolysis observed in the HbKB/C compound
heterozygote is likely to be secondary to the acceleration of Hb
crystallization.

.0154
HEMOGLOBIN LA DESIRADE
HBB, ALA129VAL

See Merault et al. (1986).

.0155
HEMOGLOBIN LAS PALMAS
HBB, SER49PHE

See Malcorra-Azpiazu et al. (1988).

.0156
HEMOGLOBIN LEIDEN
HBB, GLU6DEL OR GLU7DEL

See De Jong et al. (1968), Juricic et al. (1983), and Schroeder et al.
(1982).

.0157
HEMOGLOBIN LINCOLN PARK
HBB/HBD ANTI-LEPORE
HBB, HBB/HBD FUSION, HBD137DEL

See Honig et al. (1978). A beta-delta (anti-Lepore) variant found in a
Mexican family, its amino acid structure of the non-alpha polypeptide
indicated a crossover between amino acids 22 and 50. Honig et al. (1978)
postulated a series of intergenic crossovers. The residue corresponding
to the 137th in the delta chain is deleted. See Hb P(Nilotic).

.0158
HEMOGLOBIN LINKOPING
HEMOGLOBIN MEILAHTI
HBB, PRO36THR

See Jeppsson et al. (1984) and Ali et al. (1988). This variant was
detected by oxygen equilibrium measurements and confirmed by IEF in
Finns with erythrocytosis (Berlin et al., 1987) and in Americans of
Finnish extraction (Jones et al., 1986). Wada et al. (1987) stated that
'in Finland, there are many patients with benign familial
erythrocytosis, some of whom have Hb Helsinki' (q.v.).

.0159
HEMOGLOBIN LITTLE ROCK
HBB, HIS143GLN

See Bromberg et al. (1973) and Francina et al. (1987). Heterozygotes
have marked erythrocytosis as in the case of Hb Chesapeake, J
(Capetown), Malmo, Rainier, Bethesda, Yakima, Kempsey, and Hiroshima.

.0160
HEMOGLOBIN LOUISVILLE
HEMOGLOBIN BUCURESTI
HBB, PHE42LEU

This hemoglobin shows decreased stability on warming to 65 degrees C and
an increased tendency to dissociate in the presence of sulfhydryl
group-blocking agents. Clinically, it results in mild hemolytic anemia.
See Keeling et al. (1971), Bratu et al. (1971), and Villegas et al.
(1989).

.0161
HEMOGLOBIN LUFKIN
HBB, GLY29ASP

See Schmidt et al. (1977) and Shimizu et al. (1988). Hb Lufkin is
unstable, causing a mild but well-compensated hemolytic anemia. It was
initially described in a black American boy from Texas. Gu et al. (1995)
found this variant in combination with HbS in a black child who had a
mild form of sickle cell disease, comparable to SC or SE disease.

.0162
HEMOGLOBIN LYON
HBB, LYS17DEL AND VAL18DEL

Deletion of beta 17-18 (lys-val). See Solal et al. (1974).

.0163
HEMOGLOBIN M (MILWAUKEE 1)
HBB, VAL67GLU

See Gerald and Efron (1961), Hayashi et al. (1969), Perutz et al.
(1972), and Horst et al. (1983). This is now usually called simply Hb M
(Milwaukee) since Hb M (Milwaukee-2) has been shown to be the same as Hb
M (Hyde Park). The family reported by Pisciotta et al. (1959) was of
Italian extraction. Hb M (Milwaukee) was also described in a German
family by Kohne et al. (1977). Oehme et al. (1983) followed the mutant
beta-globin gene through 3 generations of this family by direct SstI
analysis at the gene level. The molecular defect is a transversion T to
A and because of the known recognition sequence of SstI, the nucleotide
sequence corresponding to amino acids 67 and 68 can be established to be
GAGCTC instead of GTGCTC.

.0164
HEMOGLOBIN M (MILWAUKEE 2)
HEMOGLOBIN M (HYDE PARK);;
HEMOGLOBIN M (AKITA)
HBB, HIS92TYR

See Pisciotta et al. (1959), Heller et al. (1966), Shibata et al.
(1968), and Stamatoyannopoulos et al. (1976). Rotoli et al. (1992)
described the case of a cyanotic 7-year-old girl who was found to have
16% methemoglobin. By molecular genetic studies, they demonstrated that
this was a case of Hb M (Hyde Park). Hutt et al. (1998) showed by DNA
sequence analysis that the mutation in M (Milwaukee-2), M (Hyde Park),
and M (Akita) are all due to a change of codon 92 from CAC (his) to TAC
(tyr).

Bird et al. (1988) reported a South African family of mixed descent in
which 12 individuals with methemoglobin of the Hyde Park type also
showed polyagglutination of the red cells. The 40-year-old proband had
mild cyanosis and splenomegaly. The characteristics of this form of
polyagglutination syndrome had not previously been reported. Red cells
did not agglutinate with Arachis hypogea, Dolichos biflorus, or Salvia
sclarea, but did show weak agglutination with Salvia horminum and BSII
(GSII), and reacted strongly with Glycine soja and Sophora japonica
lectins. BSI (GSI) lectin agglutinated group A but not group O cells.
Bird et al. (1988) concluded that it was unlikely that this association
between polyagglutination and the variant hemoglobin resulted from a
single genetic mutation. Rather, the association may have been due to
red cell denaturation and abnormal bond formation between this
hemoglobin and alpha-sialoglycoprotein molecules in red blood cells.

.0165
HEMOGLOBIN M (SASKATOON)
HEMOGLOBIN M (ARHUS);;
HEMOGLOBIN M (CHICAGO);;
HEMOGLOBIN M (EMORY);;
HEMOGLOBIN M (ERLANGEN);;
HEMOGLOBIN M (HAMBURG);;
HEMOGLOBIN M (HIDA);;
HEMOGLOBIN M (HORLEIN-WEBER);;
HEMOGLOBIN M (KURUME);;
HEMOGLOBIN M (LEIPZIG);;
HEMOGLOBIN M (NOVI SAD);;
HEMOGLOBIN M (RADOM)
HBB, HIS63TYR

This was the abnormal hemoglobin in the family with autosomal dominant
cyanosis reported by Baltzan and Sugarman (1950). See Horlein and Weber
(1948), Heck and Wolf (1958), Gerald and George (1959), Gerald and Efron
(1961), Shibata et al. (1961, 1965), Heller (1962), Josephson et al.
(1962), Hanada et al. (1964), Murawski et al. (1965), Hobolth (1965),
Betke et al. (1966), Efremov et al. (1974), Kohne et al. (1975), and
Baine et al. (1980). Suryantoro et al. (1995) described the his63-to-tyr
mutation in an Indonesian boy with methemoglobinemia and mild hemolysis.
The mutation was inherited from the mother. The report further
demonstrated the worldwide distribution of Hb M-Saskatoon.

.0166
HEMOGLOBIN MACHIDA
HBB, GLU6GLN

See Harano et al. (1982).

.0167
HEMOGLOBIN MADRID
HBB, ALA115PRO

The hemoglobin Madrid variant was first discovered by Outeirino et al.
(1974) in a Spanish patient whose parents did not carry the abnormality.
A second case was observed in an American black teenager by Molchanova
et al. (1993); although there was a family history of chronic hemolytic
anemia, none of the family members was available for evaluation. Kim et
al. (2000) described Hb Madrid in a Korean family with chronic hemolytic
anemia. The amino acid substitution was due to a change at codon 115
from GCC (ala) to CCC (pro).

.0168
HEMOGLOBIN MALAY
BETA-PLUS-THALASSEMIA;;
BETA-MALAY-THALASSEMIA
HBB, ASN19SER

Yang et al. (1989) found an A-to-G change in codon 19 resulting in
beta-plus-thalassemia (613985) in a Malaysian.

.0169
HEMOGLOBIN MALMO
HBB, HIS97GLN

See Lorkin and Lehmann (1970), Fairbanks et al. (1971), Boyer et al.
(1972), Berglund (1972), and Berglund and Linell (1972).

Landin et al. (1996) found this hemoglobin variant with increased oxygen
affinity causing erythrocytosis in 2 apparently unrelated Swedish
families. In 1 family, the his97-to-gln substitution was caused by a
change from CAC-to-CAA; in the other family a CAC-to-CAG change was
found.

.0170
HEMOGLOBIN MAPUTO
HBB, ASP47TYR

See Marinucci et al. (1983).

.0171
HEMOGLOBIN MARSEILLE
HEMOGLOBIN LONG ISLAND
HBB, NH2 EXTENSION, HIS2PRO

In this abnormal hemoglobin, found by isoelectric focusing in a
hematologically normal though diabetic Maltese woman living in
Marseille, Blouquit et al. (1984, 1985) demonstrated a double
abnormality: a methionyl residue extending the NH2 terminus. This is an
example of the increasing number of hemoglobin variants detected in the
course of HbA1c evaluation in diabetics. Without DNA data, the authors
concluded that proline in position 2 constitutes a steric impairment to
the methionyl peptidase that normally eliminates the initiating
methionine. The same hypothesis has been invoked to explain the apparent
persistence of the initiator methionyl residue in naturally occurring
proteins with a met-X sequence at the NH2-terminus, X being either a
charged amino acid or a proline. Initial sequence, with abnormal
residues in parentheses, equals H2N-(met)-val-(pro)-leu-thr-glu-glu-.
Prchal et al. (1986) showed that the only lesion in DNA is an
adenine-to-cytosine transversion in the second codon. Also see Barwick
et al. (1985). Boi et al. (1989) detected this variant in Australia in
the course of monitoring glycated hemoglobin (HbA1c) in diabetics. It
causes a discrepancy between the HbA1c measurement and the clinical
state of the diabetic patient.

.0172
HEMOGLOBIN MASUDA
HBB, LEU114MET AND GLY119ASP

See Ohba et al. (1989).

.0173
HEMOGLOBIN MATERA
HBB, MET55LYS

Sciarratta and Ivaldi (1990) discovered this electrophoretically
slow-moving variant in an Italian family. Numerous red cells contained
inclusion bodies, and heat and isopropanol tests demonstrated decreased
stability of the hemoglobin.

.0174
HEMOGLOBIN MEQUON
HBB, PHE41TYR

See Buckett et al. (1974).

.0175
HEMOGLOBIN MCKEES ROCKS
HBB, TYR145TER

The beta chain is only 144 amino acids long. The codon for beta 145 tyr
has been changed to a terminator. Polycythemia is the clinical
manifestation. See Winslow et al. (1975) and Rahbar et al. (1983).

.0176
HEMOGLOBIN MINNEAPOLIS-LAOS
HBB, PHE118TYR

See Hedlund et al. (1984).

.0177
HEMOGLOBIN MISSISSIPPI
HEMOGLOBIN MS
HBB, SER44CYS

See Adams et al. (1985). Hemoglobin Mississippi has anomalous properties
that include disulfide linkages with normal beta-, delta-, gamma-, and
alpha-chains, and the formation of high molecular weight multimers.
Heterozygotes for Hb MS are clinically and hematologically normal and
heterozygotes for the beta-plus-thalassemia gene have mild microcytic
anemia; however, the proband in the family initially discovered by
Steinberg et al. (1987) had all the hematologic features of thalassemia
intermedia in the compound heterozygous state. Steinberg et al. (1987)
suggested that the unexpectedly severe clinical expression in the mixed
heterozygote, as they called the state, may result from the proteolytic
digestion of Hb MS as well as the excessive alpha-chains characteristic
of beta-plus-thalassemia.

.0178
HEMOGLOBIN MITO
HBB, LYS144GLU

See Harano et al. (1985).

.0179
HEMOGLOBIN MIYADA
HBB/HBD ANTI-LEPORE
HBB, HBB/HBD FUSION

This is a beta-delta fusion variant, the complement of hemoglobin
Lepore. For explanation, see hemoglobin P (Congo) (141900.0214). From a
DNA sequence analysis of the Hb Miyada gene, Kimura et al. (1984)
concluded that the shift from the 5-prime beta-globin gene to the
3-prime delta-globin gene occurred somewhere in a homologous sequence
region between the third nucleotide of codon 17 and the second
nucleotide of codon 21 of these 2 genes.

.0180
HEMOGLOBIN MIYASHIRO
HBB, VAL23GLY

See Nakatsuji et al. (1981) and Ohba et al. (1984).

.0181
HEMOGLOBIN MIZUHO
HBB, LEU68PRO

See Ohba et al. (1977). Keeling et al. (1991) observed this variant in a
Caucasian boy from Kentucky.

As noted by Harthoorn-Lasthuizen et al. (1995), Hb Mizuho is one of the
more markedly unstable hemoglobin variants and is difficult to detect
both by protein analysis and by sequencing of the amplified beta chain.
The instability is due to the introduction of a proline residue in helix
E, of which 5 residues form part of the heme contact.
Harthoorn-Lasthuizen et al. (1995) identified a fourth case in a Dutch
boy.

.0182
HEMOGLOBIN MIZUNAMI
HBB, PHE83SER

See Shibata et al. (1980).

.0183
HEMOGLOBIN MOBILE
HBB, ASP73VAL

See Schneider et al. (1975) and Converse et al. (1985).

.0184
HEMOGLOBIN MORIGUCHI
HBB, HIS97TYR

See Ohba et al. (1989).

.0185
HEMOGLOBIN MOSCVA
HBB, GLY24ASP

See Idelson et al. (1974).

.0186
HEMOGLOBIN MOZHAISK
HBB, HIS92ARG

See Spivak et al. (1982).

.0187
HEMOGLOBIN N, BETA TYPE
HBB, LYS95ASP

Fast hemoglobin. See Ager and Lehmann (1958), Chernoff and Weichselbaum
(1958), and Gammack et al. (1961).

.0188
HEMOGLOBIN N (BALTIMORE)
HEMOGLOBIN N (JENKINS);;
HEMOGLOBIN JENKINS;;
HEMOGLOBIN HOPKINS 1;;
HEMOGLOBIN KENWOOD
HBB, LYS95GLU

See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967),
Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes
the concentration of Hb N (Baltimore) is the same as that of HbA.
Hemoglobin Kenwood was previously reported incorrectly as having either
aspartic acid or glutamic acid at beta 143. See personal communication
from Heller in Hamilton et al. (1969).

.0189
HEMOGLOBIN N (MEMPHIS)
HBB, LYS95GLX

See Schroeder and Jones (1965).

.0190
HEMOGLOBIN N (SEATTLE)
HBB, LYS61GLU

See Jones et al. (1968).

.0191
HEMOGLOBIN N (TIMONE)
HBB, LYS8GLU

See Lena-Russo et al. (1989).

.0192
HEMOGLOBIN NAGASAKI
HBB, LYS17GLU

See Maekawa et al. (1970). Nakamura et al. (1997) identified a second
case in a Japanese family. The proband was a 47-year-old diabetic male.
The anomaly was identified during the HPLC assay for HBA1c. The abnormal
beta chain comprised about 44% of the total beta chain as opposed to 30%
in the previous report.

.0193
HEMOGLOBIN NAGOYA
HBB, HIS97PRO

Hb Nagoya is an unstable hemoglobin found in father and son in Japan
(Ohba et al., 1985).

.0194
HEMOGLOBIN NEVERS
HBB, TYR130SER

During an investigation for erythrocytosis, Keclard et al. (1990) found
this electrophoretically silent beta chain variant in a French-Caucasian
male. The sister, mother, and grandmother carried the same abnormal
hemoglobin in heterozygous state. The mother showed mild erythrocytosis.

.0195
HEMOGLOBIN NEW MEXICO
HBB, PRO100ARG

See Moo-Penn et al. (1985).

.0196
HEMOGLOBIN NEW YORK
HEMOGLOBIN KAOHSIUNG
HBB, VAL113GLU

This variant was found in a Chinese-American family. See Ranney et al.
(1967), Kendall and Pang (1980), Saenz et al. (1980), and Todd et al.
(1980).

.0197
HEMOGLOBIN NEWCASTLE
HBB, HIS92PRO

See Finney et al. (1975).

.0198
HEMOGLOBIN NITEROI
HBB, PHE42DEL, GLU43DEL, SER44DEL

Deletion of phenylalanine, glutamic acid and serine at either beta 42-44
or beta 43-45. See Praxedes et al. (1972).

.0199
HEMOGLOBIN NORTH CHICAGO
HBB, PRO36SER

Increased oxygen affinity. Discovered in a 52-year-old man treated since
age 20 years for polycythemia vera with various measures including
several courses of 32(P) (Rahbar et al., 1985).

.0200
HEMOGLOBIN NORTH SHORE
HEMOGLOBIN NORTH SHORE-CARACAS
HBB, VAL134GLU

See Arends et al. (1977), Brennan et al. (1977), Adams et al. (1982),
and Gurney et al. (1987).

.0201
HEMOGLOBIN NOTTINGHAM
HBB, VAL98GLY

See Gordon-Smith et al. (1973) and Orringer et al. (1978). The patient
of Orringer et al. (1978) was a 7-year-old boy with severe hemolytic
anemia in whom great improvement in clinical status, including rate of
growth, was noted 1 year after he underwent a splenectomy and
cholecystectomy. Cepreganova et al. (1992) described severe hemolytic
anemia in a 7-year-old Canadian boy with Hb Nottingham. Brabec et al.
(1994) reported a fourth case in an 8-year-old girl in the Czech
Republic with severe hemolytic anemia.

.0202
HEMOGLOBIN O (ARAB)
HEMOGLOBIN EGYPT
HBB, GLU121LYS

This hemoglobin has been found in American blacks, Bulgarians, and Arabs
(Kamel et al., 1967). Little et al. (1980) illustrated the fact that
point mutation can be recognized by the change in susceptibility to
cleavage by specific restriction endonucleases. The examples were: Hb
O(Arab) with EcoRI, Hb J(Broussais) with HindIII, and Hb F(Hull) with
EcoRI. The sickle cell mutation eliminates a site for MnlI. See Ramot et
al. (1960), Kamel et al. (1966), Vella et al. (1966), Milner et al.
(1970), and Charache et al. (1977).

.0203
HEMOGLOBIN OCHO RIOS
HBB, ASP52ALA

See Beresford et al. (1972).

.0204
HEMOGLOBIN OHIO
HBB, ALA142ASP

High oxygen affinity leads to erythrocytosis. See Moo-Penn et al.
(1980).

.0205
HEMOGLOBIN OKALOOSA
HBB, LEU48ARG

See Charache et al. (1973).

.0206
HEMOGLOBIN OKAYAMA
HBB, HIS2GLN

See Harano et al. (1983).

.0207
HEMOGLOBIN OKAZAKI
HBB, CYS93ARG

See Harano et al. (1984).

.0208
HEMOGLOBIN OLMSTED
HBB, LEU141ARG

See Fairbanks et al. (1969) and Lorkin and Lehmann (1970). Thuret et al.
(1996) described a second case of this unstable hemoglobin. The clinical
course of a 12-year-old boy was characterized by severe hemolytic anemia
leading to splenectomy and cholecystectomy at the age of 3.5 years.
Priapism occurred 8 years after splenectomy, during a hemolytic febrile
episode, and required aspiration of the corpora cavernosa. Splenectomy
in cases of chronic hemolytic anemia due to an unstable hemoglobin
lowers the frequency and severity of acute hemolytic attacks but
vascular complications often occur. The original patient with Hb
Olmsted, described by Fairbanks et al. (1969) died of chronic pulmonary
disease with pulmonary hypertension at age 36 years. The patient
reported by Thuret et al. (1996) had a French mother and Spanish father.

.0209
HEMOGLOBIN OLOMOUC
HBB, ALA86ASP

This beta-chain variant, associated with erythrocytosis, was first
discovered in a member of a Czechoslovakian family (Indrak et al.,
1987). Tagawa et al. (1992) found the same mutation in a Japanese
family.

.0210
HEMOGLOBIN OLYMPIA
HBB, VAL20MET

Since GUG to AUG is the only single base change that can result in this
substitution, the codon for beta 20 can be uniquely identified as GUG.
See Stamatoyannopoulos et al. (1973) and Weaver et al. (1984). Berlin
and Wranne (1989) described hemoglobin Olympia in a Swedish family.

.0211
HEMOGLOBIN OSLER
HEMOGLOBIN NANCY;;
HEMOGLOBIN FORT GORDON
HBB, TYR145ASN-TO-ASP

Compensatory erythrocytosis results from its high oxygen affinity. See
Charache et al. (1975), Gacon et al. (1975), Kleckner et al. (1975), and
Butler et al. (1982).

Kattamis et al. (1997) found hemoglobin Osler in 2 members of an African
American family with erythrocytosis. Sequence analysis of DNA from the
proband showed heterozygosity for a T-to-A transversion at the first
position of codon 145 in the HBB gene, which resulted in the
substitution of an asparagine for normal tyrosine. The second cycle of
C-terminal amino acid sequence analysis of a mixture of alpha- and
beta-globin chains showed tyrosine, aspartic acid, and small amounts of
asparagine. Collectively, these results were interpreted as indicating
the existence of a mutation at codon 145 of the HBB gene, which codes
for asparagine instead of tyrosine, and that asparagine then undergoes
initial posttranslational deamidation to aspartic acid. Thus the
mutation is tyr145asn, not tyr145asp, as initially thought.
Posttranslational modifications had been described in 4 other
beta-globin chains and 2 alpha-globin chain variants: Hb Providence
(141900.0227), Hb Redondo, or Isehara (141900.0404), Hb La Roche-sur-Yon
(141900.0482), Hb J (Singapore) (141800.0075), Hb Wayne (141850.0004),
and the only variant in which the posttranslational modification does
not involve an asn-to-asp substitution, Hb Bristol (val167met-asp;
141900.0030).

.0212
HEMOGLOBIN OSU CHRISTIANSBORG
HBB, ASP52ASN

Konotey-Ahulu et al. (1971) first observed this nonpathologic mutant in
a Ghanaian patient with Hb S (141900.0243). By molecular analysis of the
HBB gene, Giordano et al. (1999) identified the same mutant in 2
unrelated families of African origin living in the Netherlands, one from
Ghana and the other from the Dominican Republic. In all carriers of both
families, the mutation was associated with haplotype 11, an infrequent
haplotype in the West African population, suggesting a single common
mutation event. Giordano et al. (1999) stated that because Hb
Osu-Christiansborg migrates at a similar rate to that of Hb S in
alkaline hemoglobin electrophoresis, it can easily be mistaken for Hb S.

Hb Osu-Christiansborg has been described in several parts of the world
and the mutation is believed to have had independent origins in these
cases. Rodrigues de Souza et al. (2004) reported the first case of Hb
Osu-Christiansborg in Brazil. The patient was a healthy 10-year-old boy,
descendant of Spanish and Brazilian Native Indians. Hematologic data
were all normal. The mutation was not found in the parents. Paternity
testing confirmed the biologic relationship between the parents and the
child, demonstrating that this was a de novo mutation.

.0213
HEMOGLOBIN P
HEMOGLOBIN P (GALVESTON)
HBB, HIS117ARG

See Silvestroni et al. (1963), Schneider et al. (1969), and Di Iorio et
al. (1975).

.0214
HEMOGLOBIN P (CONGO)
HBB/HBD ANTI-LEPORE
HBB, HBB/HBD FUSION

This is a beta-delta fusion variant, the complement of hemoglobin
Lepore. Unlike the delta-beta fusion product of Lepore hemoglobin, the
non-alpha chain resembles beta at the NH2-end. Furthermore, HbA2 is
present in normal concentrations and both HbA and HbS (or other beta
variant) can be present in the patient heterozygous for hemoglobin P
(Congo). The explanation for the origin of hemoglobin Lepore and
hemoglobin P (Congo) (nonhomologous pairing and unequal crossing-over)
is diagrammed in Fig. 2.20 (p. 41) of McKusick (1969). The fusion occurs
between beta 22 and delta 116 (Lehmann and Charlesworth, 1970). See
Dherte et al. (1959), Lehmann et al. (1964), Lambotte-Legrand et al.
(1960), and Gammack et al. (1961).

.0215
HEMOGLOBIN P (NILOTIC)
HBB/HBD ANTI-LEPORE
HBB, HBB/HBD FUSION

This is a beta-delta fusion product like Hb P (Congo) and Hb Miyada. The
fusion site is beta 22 to delta 50. Thus, Hb P(Nilotic) is identical to
Hb Lincoln Park (141900.0157) except for deletion of delta residue 137
in Hb Lincoln Park. Thus, it is the complement of Hb Lepore (Hollandia).
See Badr et al. (1973). Among 8 chromosomes carrying the Hb P (Nilotic)
hybrid gene, Lanclos et al. (1987) found only 1 haplotype.

.0216
HEMOGLOBIN PALMERSTON NORTH
HBB, VAL23PHE

See Brennan et al. (1982).

.0217
HEMOGLOBIN PASADENA
HBB, LEU75ARG

See Johnson et al. (1980) and Rahbar et al. (1988).

.0218
HEMOGLOBIN PERTH
HEMOGLOBIN ABRAHAM LINCOLN;;
HEMOGLOBIN KOBE
HBB, LEU32PRO

This is an unstable hemoglobin resulting in hemolytic anemia. See
Jackson et al. (1973), Honig et al. (1973), Rousseaux et al. (1980), and
Shibata et al. (1980).

.0219
HEMOGLOBIN PETERBOROUGH
HBB, VAL111PHE

See King et al. (1972).

Nakanishi et al. (1998) provided the second report of Hb Peterborough
and the first of its occurrence in Japan.

.0220
HEMOGLOBIN PHILLY
HBB, TYR35PHE

An unstable hemoglobin leading to hemolytic anemia. No electrophoretic
abnormality. See Rieder et al. (1969) and Asakura et al. (1981).

.0221
HEMOGLOBIN PIERRE-BENITE
HBB, GLU90ASP

See Baklouti et al. (1988).

.0222
HEMOGLOBIN PITIE-SALPETRIERE
HBB, VAL34PHE

Associated with erythrocytosis. See Blouquit et al. (1980).

.0223
HEMOGLOBIN POISSY
HBB, GLY56ARG AND ALA86PRO

See Lacombe et al. (1985).

.0224
HEMOGLOBIN PORTO ALEGRE
HBB, SER9CYS

This hemoglobin has an extra reactive thiol group because of the
substitution of cysteine for serine. Octamers and dodecamers form in
hemolysates of heterozygotes and homozygotes, respectively, on standing,
through linkage between tetramers by disulfide bridges. See Tondo et al.
(1963), Bonaventura and Riggs (1967), Seid-Akhavan et al. (1973), and
Tondo (1977).

Salzano (2000) tabulated the Hbb variants observed in Latin America and
provided further information on Hb Porto Alegre, which had been
discovered by his group in a family of Portuguese descent living in the
Brazilian city of that name. Substitution of cysteine for serine at the
ninth residue of the chain created a sulfhydryl group on the surface of
the molecule, allowing formation of intermolecular disulfide bonds.
However, polymerization occurs in vitro but not in vivo, and the variant
hemoglobin leads to no clinical problems. Lack of polymerization in vivo
may be because of a compensatory synthesis of glutathione reductase.

.0225
HEMOGLOBIN POTOMAC
HBB, GLU101ASP

See Charache et al. (1978) and Lacombe et al. (1987).

.0226
HEMOGLOBIN PRESBYTERIAN
HBB, ASN108LYS

See Moo-Penn et al. (1978), Horst et al. (1983), and Villegas et al.
(1986). Using PCR and direct sequencing, Schnee et al. (1990)
demonstrated that the molecular defect is a C-to-G substitution in codon
108; this eliminates an MaeII restriction site.

The beta variant lys108 enhances the stability of hemoglobin in the
deoxy-state, conferring low affinity for oxygen binding in vitro. Suzuki
et al. (2002) generated mutant mice carrying the Presbyterian mutation
at the beta-globin locus by a targeted knockin strategy. Heterozygous
mice showed the expression of Hb Presbyterian in 27.7% of total
peripheral blood without any hematologic abnormalities, which well
mimicked human cases. On the other hand, homozygous mice exclusively
expressed Hb Presbyterian in 100% of peripheral blood associated with
hemolytic anemia, Heinz body formation, and splenomegaly. Hb
Presbyterian showed instability in an in vitro precipitation assay.
Erythrocytes from homozygous mice showed a shortened life span when
transfused into wildtype mice, confirming that the knocked-in mutation
of lys108 caused hemolysis in homozygous mice. Suzuki et al. (2002)
stated that this was the first report on the hemolytic anemia of
unstable hemoglobin in an animal model. The results confirmed the notion
that the higher ratio of an unstable variant beta-globin chain in
erythrocytes triggers the pathologic precipitation and induces hemolysis
in abnormal hemoglobinopathies.

.0227
HEMOGLOBIN PROVIDENCE
HBB, LYS82ASX

See Moo-Penn et al. (1976), Charache et al. (1977), and Bardakdjian et
al. (1985).

.0228
HEMOGLOBIN PYRGOS
HBB, GLY83ASP

See Tatsis et al. (1972) and Yamada et al. (1977). Schiliro et al.
(1991) found this hemoglobin variant in a mother and son in Sicily who
were both clinically and hematologically normal.

.0229
HEMOGLOBIN QUIN-HAI
HBB, LEU78ARG

See Pong et al. (1983).

.0230
HEMOGLOBIN RADCLIFFE
HBB, ASP99ALA

Cause of polycythemia. See Weatherall et al. (1977).

.0231
HEMOGLOBIN RAHERE
HBB, LYS82THR

See Lorkin et al. (1975) and Sugihara et al. (1985). Beta 82 is at the
binding site of 2,3-diphosphoglycerate. Hb Rahere is accompanied by
erythrocytosis.

.0232
HEMOGLOBIN RAINIER
HBB, TYR145CYS

See Stamatoyannopoulos et al. (1968), Adamson et al. (1969),
Stamatoyannopoulos and Yoshida (1969), Greer and Perutz (1971), Hayashi
et al. (1971), and Salhany (1972). Hb Rainier causes erythrocytosis and
is the only adult hemoglobin that is alkali-resistant. See Hb Bethesda
(141900.0022), with which Rainier was confused earlier. Peters et al.
(1985) studied a hemoglobin mutation induced by ethylnitrosourea in the
mouse. Substitution of cysteine for tyrosine at codon 145 of the HBB
gene was demonstrated by amino acid analysis. They proposed that an
A-to-G transition in the tyrosine codon (TAC-to-TGC) had occurred. The
mouse was polycythemic.

Carbone et al. (1999) identified a high oxygen affinity hemoglobin
variant in a 53-year-old male from Naples, Italy, who suffered from
pulmonary thromboembolism and polycythemia. Characterization of this
variant at the protein level detected the presence of Hb Rainier. The
mutation resulted from an A-to-G transition at the second position of
codon 145 of the HBB gene, resulting in a tyr145-to-cys substitution.

.0233
HEMOGLOBIN RALEIGH
HBB, VAL1ALA

Substitution of acetylalanine for valine at beta 1. See Moo-Penn et al.
(1977).

.0234
HEMOGLOBIN RANDWICK
HBB, TRP15GLY

See Gilbert et al. (1988).

.0235
HEMOGLOBIN REGINA
HBB, LEU96VAL

See Devaraj et al. (1985). Bisse et al. (1991) reported the second
affected family. The hemoglobin variant was associated with high oxygen
affinity and erythrocytosis.

.0236
HEMOGLOBIN RICHMOND
HBB, ASN102LYS

See Efremov et al. (1969) and Winslow and Charache (1975).

.0237
HEMOGLOBIN RIO GRANDE
HBB, LYS8THR

See Moo-Penn et al. (1983).

.0238
HEMOGLOBIN RIVERDALE-BRONX
HBB, GLY24ARG

See Ranney et al. (1968).

.0239
HEMOGLOBIN RIYADH
HEMOGLOBIN KARATSU
HBB, LYS120ASN

See Budge et al. (1977), El-Hazmi and Lehmann (1977), Miyaji et al.
(1977), and Pinkerton et al. (1979).

.0240
HEMOGLOBIN ROSEAU-POINTE A PITRE
HBB, GLU90GLY

See Merault et al. (1985).

.0241
HEMOGLOBIN ROTHSCHILD
HBB, TRP37ARG

See Gacon et al. (1977) and Danish et al. (1982). Kavanaugh et al.
(1992) reported x-ray crystallographic studies.

.0242
HEMOGLOBIN RUSH
HBB, GLU101GLN

See Adams et al. (1974).

.0243
HEMOGLOBIN S
SICKLE CELL ANEMIA, INCLUDED;;
MALARIA, RESISTANCE TO, INCLUDED
HBB, GLU6VAL

The change from glutamic acid to valine in sickle hemoglobin was
reported by Ingram (1959). Ingram (1956) had reported that the
difference between hemoglobin A and hemoglobin S lies in a single
tryptic peptide. His analysis of this peptide, peptide 4, was possible
by the methods developed by Sanger for determining the structure of
insulin and Edman's stepwise degradation of peptides.

Kan and Dozy (1978) used the HpaI restriction endonuclease polymorphism
(actually the linkage principle) to make the prenatal diagnosis of
sickle cell anemia (603903). As described in 143020, when 'normal' DNA
is digested with HpaI, the beta-globin gene is contained in a fragment
7.6 kilobases long. In persons of African extraction 2 variants were
detected, 7.0 kb and 13.0 kb long. These variants resulted from
alteration in the normal HpaI recognition site 5000 nucleotides to the
3-prime side of the beta-globin gene. The 7.6 and 7.0 kb fragments were
present in persons with Hb A, while 87% of persons with Hb S had the
13.0 kb variant. The method is sufficiently sensitive that the cells in
15 ml of uncultured amniotic fluid sufficed. Restriction enzyme studies
indicate that whereas Hb S and Hb C originated against the same genetic
background (as independent mutations) and the Hb S in the Mediterranean
littoral probably is the same mutation as the West African Hb S, Hb S in
Asia is apparently a separate mutation. It does not show association
with the noncoding polymorphism (Kan and Dozy, 1979).

Mears et al. (1981) used the linkage of the sickle gene with restriction
polymorphisms to trace the origin of the sickle gene in Africa. They
found evidence that 2 different chromosomes bearing sickle genes were
subjected to selection and expansion in 2 physically close but
ethnically separate regions of West Africa, with subsequent diffusion to
other areas of Africa. The restriction enzyme MnlI recognizes the
sequence G-A-G-G, which also is eliminated by the sickle mutation. The
MstII enzyme recognizes the sequence C-C-T-N-A-G-G. Predictably, the
resulting fragments are larger than those produced by some other
enzymes, and MstII is, therefore, particularly useful in prenatal
diagnosis (Wilson et al., 1982). The sickle cell mutation can be
identified directly in DNA by use of either of 2 restriction
endonucleases--DdeI or MstII (Geever et al., 1981; Kazazian, 1982). The
nucleotide substitution alters a specific cleavage site recognized by
each of these 2 enzymes. The fifth, sixth, and seventh codons of Hb A
are CCT-GAG-GAG; in Hb S, they are CCT-GTG-GAG. The recognition site for
DdeI is C-T-N-A-G, in which N = any nucleoside. Chang and Kan (1982) and
Orkin et al. (1982) found that the assay using the restriction enzyme
MstII is sufficiently sensitive that it can be applied to uncultured
amniotic fluid cells. The enzyme DdeI requires that the amniotic cells
be cultured to obtain enough DNA for the assay.

Antonarakis et al. (1984) applied the Kazazian haplotype method to the
study of the origin of the sickle mutation in Africans. Among 170 beta-S
bearing chromosomes, 16 different haplotypes of polymorphic sites were
found. The 3 most common beta-S haplotypes, accounting for 151 of the
170, were only rarely seen in chromosomes bearing the beta-A gene in
these populations (6 out of 47). They suggested the occurrence of up to
4 independent mutations and/or interallelic gene conversions. By
haplotype analysis of the beta-globin gene cluster in cases of Hb S in
different parts of Africa, Pagnier et al. (1984) concluded that the
sickle mutation arose at least 3 times on separate preexisting
chromosomal haplotypes. The Hb S gene is closely linked to 3 different
haplotypes of polymorphic endonuclease restriction sites in the
beta-like gene cluster: one prevalent in Atlantic West Africa, another
in central West Africa, and the last in Bantu-speaking Africa
(equatorial, East, and southern Africa). Nagel et al. (1985) found
hematologic differences between the first 2 types explicable probably by
differences in fetal hemoglobin production. Ramsay and Jenkins (1987)
found that 20 of 23 sickle-associated haplotypes in southern-African
Bantu-speaking black subjects were the same as those found commonly in
the Central African Republic, a finding providing the first convincing
biologic evidence for the common ancestry of geographically widely
separated speakers of languages belonging to the Bantu family. The 3
haplotypes seen with the beta-S gene in Africa are referred to as
Senegal, Benin, and Bantu. The 'Bantu line' extends across the waist of
Africa; south of the line, Bantu languages are spoken. Based on their
study, Ramsay and Jenkins (1987) suggested that the sickle cell mutation
arose only once in the Bantu speakers, presumably in their nuclear area
of origin, before the Bantu expansion occurred about 2,000 years ago. In
Yaounde, the capital city of Cameroon, Lapoumeroulie et al. (1992)
observed a novel RFLP pattern in the study of beta-S chromosomes. This
chromosome contained an A-gamma-T gene and the RFLP haplotype was
different from all the other beta(S) chromosomes in both the 5-prime and
3-prime regions. All the carriers of this specific chromosome belonged
to the Eton ethnic group and originated from the Sanaga river valley.

Kulozik et al. (1986) found that the sickle gene in Saudi Arabia and on
the west and east coasts of India exists in a haplotype not found in
Africa. They concluded that the data are most consistent with an
independent Asian origin of the sickle cell mutation. The distribution
of the Asian beta-S-haplotype corresponded to the reported geographic
distribution of a mild clinical phenotype of homozygous SS disease.
Ragusa et al. (1988) found that the beta-S gene in Sicily is in linkage
disequilibrium with the Benin haplotype, the same haplotype observed
among sickle cell anemia patients from Central West Africa. In addition,
this haplotype is either nonexistent or very rare among nonsickling
Sicilian persons. They concluded that the beta-S gene was introduced
into Sicily from North Africa and that the gene flow originated in
Central West Africa, traveling north through historically well-defined
trans-Saharan commercial routes.

Zeng et al. (1994) indicated that 5 different haplotypes associated with
Hb S had been described, 4 in Africa (Bantu, Benin, Senegal, and
Cameroon) and 1 found in both India and Saudi Arabia (Chebloune et al.,
1988). There is a correlation between disease severity and haplotype for
at least the 2 extremes of severity: patients with the Indian/Arabian
haplotype have the mildest course of disease, while those with the Bantu
haplotype exhibit the most severe course. Nucleotide -530 is a binding
site for a protein called BP1 (601911), which may be a repressor of the
HBB gene. BP1 binds with the highest affinity to the Indian haplotype
sequence and with the weakest affinity to the Bantu sequence, which
might explain the differences in clinical course in these different
population groups. Zeng et al. (1994) demonstrated the same sequence at
-530 bp in patients with the Arabian haplotype as in Indian sickle cell
anemia patients. This supports the idea of a common origin of the sickle
cell mutation in individuals in India and Saudi Arabia.

Sammarco et al. (1988) presented further strong evidence that the Hb S
gene in Sicily was brought by North African populations, probably during
the Muslim invasions.

Currat et al. (2002) studied the genetic diversity of the beta-globin
gene cluster in an ethnically well-defined population, the Mandenka from
eastern Senegal. The absence of recent admixture and amalgamation in
this population permitted application of population genetics methods to
investigate the origin of the sickle cell mutation (Flint et al., 1993)
and to estimate its age. The frequency of the sickle cell mutation in
the Mandenka was estimated as 11.7%. The mutation was found strictly
associated with the single Senegal haplotype. Approximately 600 bp of
the upstream region of the beta-globin gene were sequenced for 94
chromosomes, showing the presence of 4 transversions, 5 transitions, and
a composite microsatellite polymorphism. The sequence of 22 chromosomes
carrying the sickle mutation was also identical to the previously
defined Senegal haplotype, suggesting that the mutation is very recent.
Maximum likelihood estimates of the age of the mutation using Monte
Carlo simulations were 45 to 70 generations (1,350-2,100 years) for
different demographic scenarios.

Embury et al. (1987) described a new method for rapid prenatal diagnosis
of sickle cell anemia by DNA analysis. The first step involved a
200,000-fold enzymatic amplification of the specific beta-globin DNA
sequences suspected of carrying the sickle mutation. Next, a short
radiolabelled synthetic DNA sequence homologous to normal beta-A-globin
gene sequences is hybridized to the amplified target sequence. The
hybrid duplexes are then digested sequentially with 2 restriction
endonucleases. The presence of the beta-A or beta-S gene sequence in the
amplified target DNA from the patient determines whether the beta-A
hybridization probe anneals perfectly or with a single nucleotide
mismatch. This difference affects the restriction enzyme digestion of
the DNA and the size of the resulting radiolabelled digestion products
which can be distinguished by electrophoresis followed by
autoradiography. The method was sufficiently sensitive and rapid that
same-day prenatal diagnosis using fetal DNA was possible. The same test
could be applied to the diagnosis of hemoglobin C disease. Hemoglobin C
(Georgetown) also sickles. See Herrick (1910), Sherman (1940), Neel
(1949), Pauling et al. (1949), Allison (1954), Ingram (1956, 1957,
1959), Chang and Kan (1981), and Shalev et al. (1988).

Barany (1991) described a new assay designed to detect single base
substitutions using a thermostable enzyme similar to the DNA polymerase
used in PCR. This enzyme, DNA ligase, specifically links adjacent
oligonucleotides only when the nucleotides are perfectly base-paired at
the junction. In the presence of a second set of adjacent
oligonucleotides, complementary to the first set and the target, the
oligonucleotide products may be exponentially amplified by thermal
cycling of the ligation reaction. Because a single base mismatch
precludes ligation and amplification, it will be easily distinguished.
Barany (1991) demonstrated the utility of the method in discriminating
between normal and sickle globin genotypes from 10 microliter blood
samples.

Prezant and Fischel-Ghodsian (1992) described a trapped-oligonucleotide
nucleotide incorporation (TONI) assay for the screening of a
mitochondrial polymorphism and also showed that it could distinguish the
genotypes of hemoglobins A/C, A/A, A/S, and S/S. The method was
considered particularly useful for diagnosing mutations that do not
produce alterations detectable by restriction enzyme analysis. It also
requires only a single oligonucleotide and no electrophoretic separation
of the allele-specific products. It represents an improved and
simplified modification of the allele-specific primer extension methods.
(TONI, the acronym for the method, is also the given name of the first
author.)

Grosveld et al. (1987) identified dominant control region (DCR)
sequences that flank the human beta-globin locus and direct high-level,
copy-number-dependent expression of the human beta-globin gene in
erythroid cells in transgenic mice. By inserting a construct that
included 2 human alpha genes and the defective human beta-sickle gene,
all driven by the DCR sequences, Greaves et al. (1990) produced 2 mice
with relatively high levels of human Hb S in their red cells. Use of
this as an animal model for the study of this disease was suggested.

Turhan et al. (2002) presented evidence suggesting that a pathogenetic
mechanism in sickle cell vasoocclusion may reside in adherent
leukocytes. Using intravital microscopy in mice expressing human sickle
hemoglobin, they demonstrated that SS red blood cells bind to adherent
leukocytes in inflamed venules, producing vasoocclusion of cremasteric
venules. SS mice deficient in P- and E-selectins, which display
defective leukocyte recruitment to the vessel wall, were protected from
vasoocclusion. Thus, drugs targeting SS RBC-leukocyte or
leukocyte-endothelial interactions might prevent or treat the vascular
complications of this disease.

Nitric oxide (NO), essential for maintaining vascular tone, is produced
from arginine by NO synthase. Plasma arginine levels are low in sickle
cell anemia, and Romero et al. (2002) reported that the sickle
transgenic mouse model has low plasma arginine. They supplemented these
mice with a 4-fold increase in arginine over a period of several months.
Mean corpuscular hemoglobin concentration decreased and the percent
high-density red cells was reduced. Romero et al. (2002) concluded that
the major mechanism by which arginine supplementation reduces red cell
density in these mice is by inhibiting the Ca(++)-activated K(+)
channel.

In a Jamaican study, Serjeant et al. (1968) described 60 patients with
homozygous sickle cell disease who were 30 years of age or older, and
Platt et al. (1994) estimated a median survival of 42 to 48 years.
Serjeant et al. (2007) stated that the sickle cell clinic at the
University of West Indies had treated 102 patients (64.7% women) who
survived beyond their 60th birthday. None of the patients received
hydroxyurea, and only 2 patients with renal impairment received regular
transfusions. The ages of the patients ranged from 60.2 to 85.6 years.
Measurement of fetal hemoglobin levels suggested that higher fetal
hemoglobin levels probably conferred protection in childhood. The major
clinical problems emerging with age were renal impairment and decreased
levels of hemoglobin.

Kwiatkowski (2005) noted that HbS homozygotes have sickle-cell disease,
whereas heterozygosity confers a 10-fold increase in protection from
life-threatening malaria (611162) and lesser protection against mild
malaria.

Cholera et al. (2008) found that P. falciparum (Pf)-infected HbA/HbS
erythrocytes did not bind to microvascular endothelial cells as well as
Pf-infected HbA/HbA erythrocytes. Reduced binding correlated with
altered display of the major Pf cytoadherence ligand on erythrocyte
membranes. Cholera et al. (2008) noted that this protective mechanism
had features in common with that of HbC (141900.0038), and they
suggested that weakening of cytoadherence interactions may influence the
degree of malaria protection in HbA/HbS children.

Modiano et al. (2008) adopted 2 partially independent haplotypic
approaches to study the Mossi population in Burkina Faso, where both the
HbS and HbC alleles are common. They showed that both alleles are
monophyletic, but that the HbC allele has acquired higher
recombinatorial and DNA slippage haplotypic variability or linkage
disequilibrium decay and is likely older than HbS. Modiano et al. (2008)
inferred that the HbC allele has accumulated mainly through recessive
rather than a semidominant mechanism of selection.

Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
subjects and transmission experiments involving 60 children and over
6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
variants HbC and HbS, which are protective against malaria, are
associated with transmission of the parasite from the human host to the
Anopheles mosquito vector. They found that HbC and HbS were associated
with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P
= 7.0 x 10(-5)) increases of parasite transmission from host to vector.
In addition, mean oocyte densities were particularly high in mosquitoes
fed from HbS carriers.

Ferreira et al. (2011) demonstrated that wildtype mice or mice
expressing normal human Hb, but not mice expressing Hbs, developed
experimental cerebral malaria (ECM) 6 to 12 days after infection with
the murine malaria parasite, Plasmodium berghei. The Hbs mice eventually
succumbed to the unrelated condition of hyperparasitemia-induced anemia.
Tolerance to Plasmodium infection was associated with high levels of
Hmox1 (141250) expression in hematopoietic cells, and mice expressing
Hbs became susceptible to ECM when Hmox1 expression was inhibited. Hbs
induced expression of Hmox1 in an Nrf2 (NFE2L2; 600492)-dependent
manner, which inhibited the production of chemokines and Cd8-positive T
cells associated with ECM pathogenesis. Ferreira et al. (2011) concluded
that sickle hemoglobin suppresses the onset of ECM via induction of
HMOX1 and the production of carbon monoxide, which inhibits the
accumulation of free heme, affording tolerance to Plasmodium infection.

Cyrklaff et al. (2011) found that HbS and HbC affect the trafficking
system that directs parasite-encoded proteins to the surface of infected
erythrocytes. Cryoelectron tomography revealed that P. falciparum
generates a host-derived actin cytoskeleton within the cytoplasm of
wildtype red blood cells that connects the Maurer clefts with the host
cell membrane and to which transport vesicles are attached. The actin
cytoskeleton and the Maurer clefts were aberrant in erythrocytes
containing HbS or HbC. Hemoglobin oxidation products, enriched in HbS
and HbC erythrocytes, inhibited actin polymerization in vitro and may
account for the protective role in malaria.

.0244
HEMOGLOBIN S (ANTILLES)
HBB, GLU6VAL AND VAL23ILE

This variant has electrophoretic mobility in standard conditions
identical to that of Hb S but shows a slightly higher pI than Hb S on
isoelectric focusing. Heterozygous carriers of this variant hemoglobin
exhibit sickling disorders. This observation may provide a clue to the
unexplained clinical sickling disorders in some A/S carriers, in whom
careful biochemical analyses may reveal other examples of double
mutations in the beta chain. See Monplaisir et al. (1986). Pagnier et
al. (1990) introduced the val23-to-ile mutation into beta-globin cDNA by
site-directed mutagenesis. The beta-globin chain was synthesized using
an expression vector and hemoglobin tetramers were reconstituted. When
mixed with equal amounts of hemoglobin S, facilitation of polymerization
was observed. Pagnier et al. (1990) listed 5 other hemoglobin variants
which contain both the sickle mutation and a second amino acid
substitution in the same beta chain.

Popp et al. (1997) bred 2 homozygous viable Hb S Antilles transgene
insertions into a strain of mice that produce hemoglobins with a higher
affinity for oxygen than normal mouse Hb. The rationale was that the
high oxygen affinity hemoglobin, the lower oxygen affinity of Hb S
Antilles, and the lower solubility of deoxygenated Hb Antilles than Hb S
would favor deoxygenation and polymerization of human Hb S Antilles in
the red cells of the high oxygen affinity mice. The investigators found
that the mice produced a high and balanced expression of human alpha and
human beta (S Antilles) globins, that 25 to 35% of their RBCs were
misshapen in vivo, and that in vitro deoxygenation of their blood
induced 30 to 50% of the RBCs to form classic elongated sickle cells
with pointed ends. The mice exhibited reticulocytosis, an elevated white
blood cell count, and lung and kidney pathology commonly found in sickle
cell patients, which should make these mice useful for experimental
studies on possible therapeutic intervention of sickle cell disease.

.0245
HEMOGLOBIN S (OMAN)
HEMOGLOBIN S/O (ARAB)
HBB, GLU6VAL AND GLU121LYS

Langdown et al. (1989) described a doubly substituted sickling
hemoglobin with the change of glu-to-val at beta 6 (141900.0243) and
glu-to-lys at beta 121 (141900.0202). The double substitution resulted
in a variant with reduced solubility and apparent increase in red cell
sickling tendency. Hemoglobin S (Oman) combines the classic Hb S
mutation (glu6 to val), with the Hb O (Arab) mutation (glu121 to lys).
Nagel et al. (1998) studied a pedigree of heterozygous carriers of Hb S
(Oman) that segregated into 2 types of patients: those expressing about
20% Hb S (Oman) and concomitant -alpha/alpha-alpha thalassemia and those
with about 14% of Hb S (Oman) and concomitant -alpha/-alpha thalassemia.
The higher expressors of Hb S (Oman) had a sickle cell anemia clinical
syndrome of moderate intensity, whereas the lower expressors had no
clinical syndrome and were comparable to the solitary case first
described in Oman. In addition, the higher expressors exhibited a unique
form of irreversibly sickled cell reminiscent of a 'yarn and knitting
needle' shape, in addition to folded and target cells. Purified Hb S
(Oman) has a C(SAT) (solubility of the deoxy polymer) of 11 g/dL, much
lower than Hb S alone (17.8 g/dL). Another double mutant, Hb S
(Antilles) (141900.0244), has a similarly low C(SAT) and much higher
expression (40 to 50%) in the trait form, but has a phenotype that is
similar in intensity to the trait form of Hb S (Oman). Nagel et al.
(1998) concluded that the pathology of heterozygous S (Oman) is the
product of recipient properties of the classic mutation which are
enhanced by the second mutation at beta-121. In addition, the syndrome
is further enhanced by a hemolytic anemia induced by the beta-121
mutation. They speculated that the hemolytic anemia results from the
abnormal association of the highly positively charged Hb S (Oman) (3
charges different from normal hemoglobin) with the RBC membrane.

To characterize better the clinical and laboratory aspects of Hb S
(Oman), also called Hb S/O (Arab), Zimmerman et al. (1999) reviewed the
Duke University Medical Center experience. They identified 13 African
American children and adults with Hb S/O (Arab), ranging in age from 2.7
to 62.5 years. All patients had hemolytic anemia with a median
hemoglobin of 8.7 gm/dL and a median reticulocyte count of 5.8%. The
peripheral blood smear typically showed sickled erythrocytes, target
cells, polychromasia, and nucleated red blood cells. All 13 patients had
had significant clinical sickling events, including acute chest syndrome
(11), recurrent vasoocclusive painful events (10), dactylitis (7),
gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis
(2), leg ulcers (2), cerebrovascular accident (1), osteomyelitis (1),
and retinopathy (1). Death had occurred in 4 patients, including 2 from
pneumococcal sepsis/meningitis at ages 5 and 10 years, 1 of acute chest
syndrome at age 14 years, and 1 of multiorgan failure at age 35 years.
Zimmerman et al. (1999) concluded that Hb S/O (Arab) disease is a severe
sickling hemoglobinopathy with laboratory and clinical manifestations
similar to those of homozygous sickle cell anemia.

.0246
HEMOGLOBIN S (PROVIDENCE)
HBB, GLU6VAL AND LYS82ASX

Gale et al. (1988) described a hemoglobin carrying 2 substitutions, the
standard substitution of Hb S (beta6 glu-to-val) and the substitution of
Hb Providence (beta82 lys-to-asx). (There is partial postsynthetic
deamination of asparagine to aspartic acid.) The double mutation is
electrophoretically silent; if hemoglobin electrophoresis alone were
done, the abnormality would be missed.

.0247
HEMOGLOBIN S (TRAVIS)
HBB, GLU6VAL AND ALA142VAL

See Moo-Penn et al. (1977).

.0248
HEMOGLOBIN SABINE
HBB, LEU91PRO

The hemoglobin is unstable, causing hemolytic anemia in the
heterozygote. See Schneider et al. (1969) and Bogoevski et al. (1983).
Hull et al. (1998) reported 2 cases of Hb Sabine, in a mother in whom
the mutation had apparently arisen de novo and her son. They stated that
more than 100 unstable hemoglobins causing hemolytic anemia had been
described. Less than 20% of the unstable hemoglobins that have been
characterized affect the alpha-globin chain.

.0249
HEMOGLOBIN SAINT JACQUES
HBB, ALA140THR

Produces erythrocytosis by alteration of the site of fixation of
2,3-diphosphoglycerate (Rochette et al., 1984).

.0250
HEMOGLOBIN SAITAMA
HBB, HIS117PRO

See Ohba et al. (1983).

.0251
HEMOGLOBIN SAKI
HBB, LEU14PRO

See Beuzard et al. (1975) and Milner et al. (1976).

.0252
HEMOGLOBIN SAN DIEGO
HBB, VAL109MET

This hemoglobin is characterized by high oxygen affinity, and
erythrocytosis is associated. See Anderson (1974), Nute et al. (1974),
and Harkness et al. (1981). Williamson et al. (1995) observed a
30-year-old man of West Indian origin who showed compound heterozygosity
for Hb San Diego and Hb S (141900.0243). He had suffered for about 6
months from severe colicky abdominal pain in episodes of several hours
duration. He showed erythrocytosis with a hemoglobin value of 18.8 g/dl.
The Hb San Diego mutation represented a GTG-to-ATG change. The Hb S
mutation was inherited from the mother; Williamson et al. (1995)
suggested that the Hb San Diego mutation occurred de novo on the
chromosome 11 derived from the father. DNA testing was consistent with
the assumed paternity. The Hb San Diego mutation occurred at a CpG
dinucleotide. It was concluded that the abdominal pain was due to
increased blood viscosity and the symptoms were relieved by venesection.

.0253
HEMOGLOBIN SANTA ANA
HBB, LEU88PRO

See Opfell et al. (1968) and Tanaka et al. (1985).

.0254
HEMOGLOBIN SAVANNAH
HBB, GLY24VAL

See Huisman et al. (1971).

.0255
HEMOGLOBIN SAVERNE
HBB, 1-BP DEL, HIS143PRO, FS

Probable frameshift mutation resulting from deletion of the second base
of the triplet coding for beta his 143; CAC becomes CCA (PRO). The last
part of the beta gene code, 143rd residue on, becomes
CAC-AGT-ATC-ACT-AAG-CTC-GCT-TTC-TTG-CTG-TCC-AAT-TTC-TAT-TAA, which reads
pro-ser-ile-thr-lys-leu-ala-phe-leu-leu-ser-asn-phe-tyr-stop (COOH).
Thus, the beta chain is 156 amino acids long rather than 146. See
Delanoe et al. (1984).

.0256
HEMOGLOBIN SEATTLE
HBB, ALA70ASP

Hemoglobin Seattle was discovered by Stamatoyannopoulos et al. (1969),
who showed that it is associated with a considerable decrease in oxygen
affinity with almost normal heme-heme interaction and normal Bohr
effect. It was their conclusion and that of Huehns et al. (1970) that
the change was ala76-to-glu. However, studies reported by Kurachi et al.
(1973) led to the conclusion that Hb Seattle has a substitution of
alanine by aspartic acid at position 70 of the beta polypeptide. Chow et
al. (1994) reported a second example of Hb Seattle in a Ukranian family.

.0257
HEMOGLOBIN SENDAGI
HEMOGLOBIN WARSAW
HBB, PHE42VAL

Ogata et al. (1986) and Honig et al. (1990) studied this unstable
variant, which has low oxygen affinity and an increased susceptibility
to methemoglobin formation.

.0258
HEMOGLOBIN SHANGHAI
HBB, GLN131PRO

The proband had chronic hemolytic anemia aggravated by oxidated drugs
and common colds. Her 10-year-old son was also affected. Biosynthesis
studies indicated a normal rate of synthesis, but relatively fast
degradation of the mutant beta chain (Zeng et al., 1987).

.0259
HEMOGLOBIN SHELBY
HEMOGLOBIN LESLIE;;
HEMOGLOBIN DEACONESS
HBB, GLN131LYS

See Felice et al. (1978), Carcassi et al. (1980), and Moo-Penn et al.
(1984). Deletion of glutamine at beta 131 in Hb Leslie was reported by
Lutcher et al. (1976) and the same deletion was reported in Hb Deaconess
by Moo-Penn et al. (1975). Later, Moo-Penn et al. (1984) showed that Hb
Deaconess and Hb Leslie are identical to Hb Shelby. All three have
substitution of lysine for glutamine at beta 131. Adachi et al. (1993)
described a compound heterozygote for Hb S and Hb Shelby. Hb Shelby,
like Hb A, can form hybrids with Hb S which participate in polymer
formation in vitro. However, Hb S/Hb Shelby hybrids copolymerize with Hb
S less than Hb A/S hybrids. The mild clinical presentation of the
patient was attributed to this fact.

.0260
HEMOGLOBIN SHEPHERDS BUSH
HBB, GLY74ASP

See White et al. (1970) and Sansone et al. (1977).

.0261
HEMOGLOBIN SHERWOOD FOREST
HBB, ARG104THR

See Ryrie et al. (1977).

Williamson et al. (1994) described a 22-year-old Pakistani male with
polycythemia associated with homozygosity for this high-affinity
hemoglobin mutant. Whereas 2 previously reported persons with the mutant
hemoglobin were heterozygotes and were hematologically normal, the
homozygous state was associated with compensatory erythrocytosis
resulting from decreased delivery of oxygen to the tissues. Both parents
and both sibs were heterozygous for the hemoglobin mutant and were
hematologically normal. This may have been the first example of a
beta-globin mutation producing polycythemia in homozygotes, but not in
heterozygotes.

.0262
HEMOGLOBIN SHOWA-YAKUSHIJI
BETA-PLUS-THALASSEMIA;;
BETA-SHOWA-YAKUSHIJI THALASSEMIA
HBB, LEU110PRO

In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988)
described a novel HBB mutation that produced the beta-thalassemia
phenotype (613985) through a posttranslational mechanism. Substitution
of proline for leucine at position 110 greatly reduced the molecular
stability of the beta-globin subunit, leading to total destruction of
the variant globin chains by proteolysis. The mutation could be
identified after digestion with the restriction enzyme MspI. They named
the variant Hb Showa-Yakushiji, after the 2 districts where the probands
resided. Other variant hemoglobins that are very unstable and lead to
thalassemia include Hb Indianapolis (141900.0117) and Hb Quong Sze
(141900.0005).

In 4 unrelated individuals in India, Edison et al. (2005) found the
hyper-unstable variant Hb Showa-Yakushiji in compound heterozygosity
with other mutations producing beta-thalassemia or with Hb E
(141900.0071). In all 4 patients, the mutation was found on the same
haplotype, which differed from the Japanese haplotype, indicating its
independent origin in India.

.0263
HEMOGLOBIN SIRIRAJ
HEMOGLOBIN G (HONAN)
HBB, GLU7LYS

This HBB gene variant was discovered in a Thai family by Tuchinda et al.
(1965) and was subsequently identified in several Chinese by Blackwell
et al. (1972). Chang et al. (1999) observed the same variant in a
Taiwanese family. DNA analysis detected a G-to-A transition at the first
base of codon 7 (GAG to AAG). This mutation creates an MboII site that
is highly specific for Hb Siriraj.

.0264
HEMOGLOBIN SOGN
HBB, LEU14ARG

Hb Sogn was first described in Norway by Monn et al. (1968). Fairbanks
et al. (1990) described the first known instances of Hb Sogn outside of
Norway, in 2 families, both of Norwegian descent. Hb Sogn has been
described in Norwegian families and in American families from the upper
midwest where settlement of Scandinavian families was common. Miller et
al. (1996) described the hemoglobin variant in a family residing in
Illinois; the proband's maternal grandfather was Norwegian. Codon 14
showed a CTG (leu)-to-CGG (arg) change. The proband married a person who
was homozygous for alpha-thalassemia-2. The couple had 2 daughters who
offered the opportunity of comparing data between Hb Sogn heterozygotes
with 4 alpha-globin genes and 3 alpha-globin genes. Mild microcytosis
and hypochromia in the father was due to the presence of alpha-thal-2
homozygosity and that in the mother to the presence of the mildly
unstable Hb Sogn. Striking microcytosis and hypochromia in 1 daughter
could be attributed to the combination of a the alpha-thal-2 trait and
Hb Sogn heterozygosity.

.0265
HEMOGLOBIN SOUTHAMPTON
HEMOGLOBIN CASPER
HBB, LEU106PRO

See Hyde et al. (1972), Jones et al. (1973), and Koler et al. (1973).

.0266
HEMOGLOBIN SOUTH FLORIDA
HBB, NH2 EXTENSION, VAL1MET, METi RETAINED

The initiator methionine residue (METi) is preserved. This variant was
first discovered in a patient who appeared to have markedly elevated Hb
A(1c) as estimated by ion exchange chromatography. Glycosylated
hemoglobin measured by a colorimetric method with thiobarbituric acid
was normal, however. If it were not for the fact that methionine is 1 of
the 4 N-terminal amino acids (alanine, glycine, serine, methionine) that
participate in acetylation, this abnormal amino acid substitution would
have gone unrecognized. Acetylation of the N-terminal methionine residue
occurs less easily than in other amino acids; thus, hemoglobin South
Florida could not be recognized by hemoglobin electrophoresis. In
contrast, acetylation of alanine in hemoglobin Raleigh is 100% and that
variant can be recognized by hemoglobin electrophoresis. See Boissel et
al. (1985) and Shah et al. (1986). Malone et al. (1987) reported a
family study. The fundamental change is not in the codon for the
initiator mutation but in the codon for the first residue for the mature
beta-globin chain, valine, which is converted to methionine. Because the
initiator methionine is retained, this methionine is substituted for
valine as residue 2 in the mature chain of Hb South Florida.

.0267
HEMOGLOBIN ST. ANTOINE
HBB, GLY74DEL AND LEU75DEL

Two amino acids, glycine and leucine, are deleted from beta 74 and 75.
See Wajcman et al. (1973).

.0268
HEMOGLOBIN ST. LOUIS
HEINZ BODY HEMOLYTIC ANEMIA
HBB, LEU28GLN

This is a form of Hb M, differing from other Hb M variants by the fact
that the substitution is not for the histidine at E7 or F8. Hb M
(Milwaukee) is another. Severe Heinz body anemia, in addition to
methemoglobinemia, is associated with Hb St. Louis. The beta heme group
is permanently in a ferric state. See Cohen-Solal et al. (1974),
Anderson (1976), Thillet et al. (1976), and Wiedermann et al. (1986).

.0269
HEMOGLOBIN ST. MANDE
HBB, ASN102TYR

This hemoglobin variant has a low oxygen affinity, resulting in
cyanosis. See Arous et al. (1981). Poyart et al. (1990) found that the
functional properties of St. Mande are intermediary between those of
normal Hb A and Hb Kansas (0.0145).

.0270
HEMOGLOBIN STANMORE
HBB, VAL111ALA

See Como et al. (1984).

.0271
HEMOGLOBIN STRASBOURG
HBB, VAL23ASP

Hb Strasbourg was first observed in a female from northern Portugal and
in 1 of her 2 children. Garel et al. (1976) incorrectly thought that the
valine at position 20 was substituted. See Forget (1977). Bisse et al.
(1998) provided information on a German family with the same
abnormality. This was the second observation of this hemoglobin variant.
The 23-year-old propositus had a hemoglobin level of 19.8 g/dl. The
variant was shown to have a high oxygen affinity. Codon 23 of the HBB
gene was changed from GTT (val) to GAT (asp).

.0272
HEMOGLOBIN SUMMER HILL
HBB, ASP52HIS

No hematologic abnormality. See Wilkinson et al. (1980) and Cin et al.
(1983).

.0273
HEMOGLOBIN SUNNYBROOK
HBB, PRO36ARG

See Ali et al. (1988).

.0274
HEMOGLOBIN SYDNEY
HBB, VAL67ALA

Like hemoglobins Koln and Genova, this hemoglobin has no electrophoretic
abnormality but is unstable, forming intracellular precipitates. See
Carrell et al. (1967) and Casey et al. (1978).

.0275
HEMOGLOBIN SYRACUSE
HBB, HIS143PRO

See Jensen et al. (1975).

.0276
HEMOGLOBIN T (CAMBODIA)
HBB, GLU26LYS AND GLU121GLN

See Barwick et al. (1985). Combines substitutions of Hb E and Hb O
(Arab): substitution of lysine for glutamic acid at beta 26 and of
glutamine for glutamic acid at beta 121.

.0277
HEMOGLOBIN TA-LI
HBB, GLY83CYS

See Blackwell et al. (1971).

.0278
HEMOGLOBIN TACOMA
HEINZ BODY HEMOLYTIC ANEMIA
HBB, ARG30SER

See Baur and Motulsky (1965), Brimhall et al. (1969), Idelson et al.
(1974), Deacon-Smith and Lee-Potter (1978), and Harano et al. (1985).

.0279
HEMOGLOBIN TAK
HBB, +8 RESIDUES

The usual terminal dipeptide 145-146 of the beta chain is lacking and is
replaced by 10 residues attached to the C-terminal end. Hemoglobin
Constant Spring is a termination defect of the alpha chain. See Flatz et
al. (1971). Characterized on the basis of amino acid analysis, this
variant was assumed to be due to an insertion of the dinucleotide CA
into codon 146, CAC-to-CA(CA)C, which abolished the normal stop codon at
position 147 and caused a frameshift with elongation of the beta chain
by 11 amino acids. The variant had previously been described in a few
Thai families. Hoyer et al. (1998) reported the DNA sequence of Hb Tak
in an individual of Cambodian descent who was a Hb E/Tak compound
heterozygote. In contrast with extended variants of the alpha-globin
gene that are expressed as alpha-thalassemias, the hematologic effect of
Hb Tak/Hb E was a mild polycythemia. The combination of Hb Tak/Hb E was
not expressed as a thalassemia.

Shih et al. (2005) reported heterozygosity for Hb Tak in a Taiwanese
individual.

.0280
HEMOGLOBIN TAKAMATSU
HBB, LYS120GLN

See Iuchi et al. (1980) and Kawata et al. (1989).

.0281
HEMOGLOBIN TAMPA
HBB, ASP79TYR

See Johnson et al. (1980).

.0282
HEMOGLOBIN TIANSHUI
HBB, GLN39ARG

In a healthy 34-year-old Chinese male of Han nationality, Li et al.
(1990) identified a hemoglobin variant and showed that it had a
replacement of glutamine by arginine at residue 39.

.0283
HEMOGLOBIN TILBURG
HBB, ASP73GLY

This hemoglobin and 3 others with a single amino acid substitution at
the same site have reduction in affinity for oxygen. See Bernini and
Giordano (1988).

.0284
HEMOGLOBIN TOCHIGI
HBB, GLY56DEL, ASN57DEL, PRO58DEL, LYS59DEL

Deletion of residues 56-59 of the beta chain. See Shibata et al. (1970).

.0285
HEMOGLOBIN TOURS
HBB, THR87DEL

See Wajcman et al. (1973).

.0286
HEMOGLOBIN TOYOAKE
HBB, ALA142PRO

See Hirano et al. (1981) and Imai et al. (1981).

.0287
HEMOGLOBIN TUBINGEN
HBB, LEU106GLN

See Kohne et al. (1976). Philippe et al. (1993) described this
hemoglobin variant, a cause of methemoglobinemia, in a 53-year-old
Belgian woman. Her father had been cyanotic throughout his life. This
was the second report of this hemoglobin variant.

.0288
HEMOGLOBIN TUNIS
HBB, PRO124SER

See Mrad et al. (1988).

.0289
HEMOGLOBIN TY GARD
HBB, PRO124GLN

See Bursaux et al. (1978).

.0290
HEMOGLOBIN VAASA
HBB, GLN39GLU

See Kendall et al. (1977).

.0291
HEMOGLOBIN VANCOUVER
HBB, ASP73TYR

See Jones et al. (1976).

.0292
HEMOGLOBIN VANDERBILT
HBB, SER89ARG

See Puett et al. (1977) and Paniker et al. (1978).

.0293
HEMOGLOBIN VICKSBURG
HBB, LEU75DEL

See Adams et al. (1981). When they failed to find evidence of deletion
of leu75 in genomic DNA, Coleman et al. (1988) proposed somatic
mutation. A more plausible explanation, perhaps, is one parallel to that
obtaining in the case of Hb Atlanta-Coventry (141900.0013).

.0294
HEMOGLOBIN VILLEJUIF
HBB, THR123ILE

This mutation was discovered as a silent and asymptomatic variant in an
87-year-old French woman who coincidentally had polycythemia vera
(Wajcman et al., 1989).. Carbone et al. (2001) reported the second
observation of this hemoglobin variant in 3 related subjects from
Montesarchio in southern Italy. The DNA change was ACC to ATC.

.0295
HEMOGLOBIN VOLGA
HEMOGLOBIN DRENTHE
HBB, ALA27ASP

See Kuis-Reerink et al. (1976), Ockelford et al. (1980), Sciarratta et
al. (1985), and Falcioni et al. (1988). Blanke et al. (1989) reported a
possible de novo mutation in a Dane.

.0296
HEMOGLOBIN WARWICKSHIRE
HBB, PRO5ARG

See Wilson et al. (1984).

.0297
HEMOGLOBIN WIEN
HBB, TYR130ASP

See Perutz and Lehmann (1968) and Lorkin et al. (1974).

.0298
HEMOGLOBIN WILLAMETTE
HBB, PRO51ARG

See Jones et al. (1976-77), Quarum et al. (1983), and Martinez and
Canizares (1984).

.0299
HEMOGLOBIN WINDSOR
HBB, VAL11ASP

Gilbert et al. (1989) found this variant in a 9-month-old child who
presented with hemolytic anemia in association with intercurrent viral
infection. Instability of the hemoglobin molecule as well as increase in
oxygen affinity was demonstrated.

.0300
HEMOGLOBIN WOOD
HBB, HIS97LEU

See Taketa et al. (1975).

.0301
HEMOGLOBIN YAKIMA
HBB, ASP99HIS

Polycythemia occurs with this hemoglobinopathy as with hemoglobin
Chesapeake. See Jones et al. (1967), Novy et al. (1967), and Osgood et
al. (1967).

.0302
HEMOGLOBIN YAMAGATA
HBB, LYS132ASN

See Harano et al. (1990).

Hemoglobin Yamagata as reported by Harano et al. (1990) was caused by a
change of codon 132 in the HBB gene from AAA (lys) to AAC (asn). Han et
al. (1996) found the same amino acid substitution in a 37-year-old
Korean woman to be caused by a change of codon 132 from AAA to AAT. No
distinctive clinical abnormalities were detected.

.0303
HEMOGLOBIN YATSUSHIRO
HBB, VAL60LEU

See Kagimoto et al. (1978).

.0304
HEMOGLOBIN YOKOHAMA
HBB, LEU31PRO

See Nakatsuji et al. (1981). Plaseska et al. (1991) described a de novo
mutation in a Yugoslavian boy with severe transfusion-dependent
hemolytic anemia. The patients of Nakatsuji et al. (1981) were a
33-year-old Japanese woman with chronic hemolytic anemia and her son
with milder symptoms.

.0305
HEMOGLOBIN YORK
HBB, HIS146PRO

See Bare et al. (1976) and Kosugi et al. (1983).

.0306
HEMOGLOBIN YOSHIZUKA
HBB, ASN108ASP

Reduced oxygen affinity like hemoglobin Kansas. See Imamura et al.
(1969).

.0307
HEMOGLOBIN YPSILANTI
HBB, ASP99TYR

Substitution in beta chain results in increased oxygen affinity leading
to erythremia and abnormal polymerization manifested in heterozygotes by
hybrid hemoglobin molecules containing both the Ypsi beta chain and the
normal beta chain. See Glynn et al. (1968) and Rucknagel (1971).

.0308
HEMOGLOBIN YUKUHASHI
HEMOGLOBIN DHOFAR
HBB, PRO58ARG

See Yanase et al. (1968) and Marengo-Rowe et al. (1968).

.0309
HEMOGLOBIN YUSA
HBB, ASP21TYR

See Harano et al. (1981) and Ohba et al. (1990).

.0310
HEMOGLOBIN ZURICH
HBB, HIS63ARG

Drug-induced hemolysis results from this variant hemoglobin. The
affinity of Hb Zurich for carbon monoxide is about 65 times that
observed in normal hemoglobin A. Carboxyhemoglobin content in persons
with Hb Zurich varied from 3.9 to 6.7% for nonsmokers and 9.8 to 19.7%
for smokers. Hemolysis was less in smokers, presumably because of
stabilization of Hb Zurich by CO. See Huisman et al. (1960), Muller and
Kingma (1961), Frick et al. (1962), Rieder et al. (1965), Dickerman et
al. (1973), Zinkham et al. (1979, 1980, 1983), Dlott et al. (1983), and
Virshup et al. (1983).

Miranda et al. (1994) identified Hb Zurich in a 38-year-old woman who
had a hemolytic crisis after administration of an antibiotic for urinary
tract infection. This hemoglobin variant was first identified by protein
analysis and then by DNA sequencing.

Aguinaga et al. (1998) studied 4 members of a Kentucky family whom they
had identified as Hb Zurich carriers. During pregnancy, the proband
developed hemolytic anemia with Heinz bodies when treated for a urinary
tract infection with sulfonamide. Because of severe anemia, the patient
was transfused several times and ultimately splenectomized. The Kentucky
family studied in this report was part of a larger kindred that was
known to contain 19 members who were Hb Zurich carriers.

Zinkham et al. (1979) demonstrated in vitro thermal denaturation of Hb
Zurich as a cause of anemia during fever.

.0311
BETA-ZERO-THALASSEMIA
HBB, LYS17TER

This variant was found in Chinese with beta-zero-thalassemia (613985).
Chang et al. (1979) and Chang and Kan (1979) presented evidence that
beta-zero-thalassemia is a nonsense mutation, the first identified in
man. By molecular hybridization they showed that the beta gene is
present. In different patients variable amounts of beta-like globin mRNA
is present. They sequenced mRNA and found that noncoding regions at both
ends were normal but at the position corresponding to amino acid no. 17,
the normal lysine codon AAG was converted to UAG, a terminator. Such a
nonsense mutation should be overcome by means of suppressor tRNA which
allows the ribosome to read through a terminator codon by inserting an
amino acid. In vitro addition of a serine suppressor tRNA from yeast
resulted in human beta-globin synthesis. Cell-free assays with
suppressor tRNAs may be useful for detecting nonsense mutations in other
human genetic disorders. Steger et al. (1993) showed that this
AAG-to-TAG nonsense mutation and the hemoglobin E mutation, common
causes of beta(+)-thalassemia and beta-zero-thalassemia in Southeast
Asia, can be detected using allele-specific PCR, known also as the
amplification refractory mutation system (ARMS).

Krawczak et al. (2000) pointed out that this was the first single
basepair substitution in a human gene underlying a genetic disorder to
be reported. Knowledge of the amino acid substitution responsible for
sickle hemoglobin permitted imperfect inference of the nucleotide change
because of redundancy of the code.

.0312
BETA-ZERO-THALASSEMIA
HBB, GLN39TER

Chehab et al. (1986) found evidence for new mutation in the codon at
beta-39 from CAG (glutamine) to the stop codon TAG. The beta-39 nonsense
mutation is the second most common beta-thalassemia (613985) lesion in
Italy, accounting for a third of cases, and the most common in Sardinia,
accounting for 90% of cases there. In Sardinia, the beta-39 mutation has
been identified with 9 different haplotypes. All this suggested to
Chehab et al. (1986) that beta-39 is a mutation hotspot. Trecartin et
al. (1981) found that the form of beta-zero-thalassemia that is
predominant in Sardinia is caused by a single nucleotide mutation at the
position corresponding to amino acid number 39 and converting a
glutamine codon (CAG) to an amber termination codon (UAG). (Epstein et
al. (1963) described 'amber' mutants of phage T4 in a frequently cited
paper in a Cold Spring Harbor Symposium on Quantitative Biology. The
origin of the unusual name 'amber' is, as Witkowski (1990) called it,
'an interesting footnote in the history of molecular biology.' Edgar
(1966) recounted that R. H. Epstein and C. M. Steinberg, then at the
California Institute of Technology, had promised Harris Bernstein, then
at Yale University, that the mutants, if any were found, would be named
after his mother. They were found and were named 'amber,' the English
equivalent of 'Bernstein.' The other 2 'stop' codons, UGA and UAA, are
sometimes referred to as 'opal' and 'ochre,' respectively.) Rosatelli et
al. (1992) used denaturing gradient gel electrophoresis (DGGE) followed
by direct sequence analysis of amplified DNA to study 3,000
beta-thalassemia chromosomes in the Sardinian population. They confirmed
that the predominant mutation, present in 95.7% of beta-thalassemia
chromosomes, was gln39-to-ter.

.0313
BETA-ZERO-THALASSEMIA
HBB, TRP15TER

The trp15-to-ter (W15X) mutation that Kazazian et al. (1984)
demonstrated in Asian beta-thalassemia (613985) patients was the result
of a TGG-to-TAG mutation. Ribeiro et al. (1992) demonstrated the
frequent occurrence in central Portugal of beta-zero-thalassemia due to
a change of codon 15 for tryptophan to a stop codon; the basis, however,
was a TGG-to-TGA mutation.

.0314
BETA-THALASSEMIA, DOMINANT INCLUSION BODY TYPE
HBB, GLU121TER

See Kazazian et al. (1986), Fei et al. (1989) and Adams et al. (1990).

Thein et al. (1990) identified the E121X mutation in 3 British families
with dominantly inherited inclusion body beta-thalassemia (603902). The
clinical features were that of a dominant dyserythropoietic anemia
associated with inclusion bodies in normoblasts. The condition was
described originally by Weatherall et al. (1973) and was previously
labeled dyserythropoietic, congenital, Irish or Weatherall type. The
original family reported by Weatherall et al. (1973) was found by Thein
et al. (1990) to carry an insertion/deletion mutation with frameshift in
the HBB gene (141900.0520).

.0315
BETA-ZERO-THALASSEMIA
HBB, TRP37TER

See Boehm et al. (1986).

.0316
BETA-ZERO-THALASSEMIA
HBB, GLU43TER

Atweh et al. (1988) described a novel nonsense mutation in a Chinese
patient with beta-zero-thalassemia (613985): a G-to-T substitution at
the first position of codon 43, which changed the glutamic acid coding
triplet (GAG) to a terminator codon (TAG). They incorrectly referred to
a patient carrying both the beta-17 and the beta-43 nonsense mutation as
being a double heterozygote rather than a compound heterozygote.

.0317
BETA-ZERO-THALASSEMIA
HBB, LYS61TER

See Gonzalez-Redondo et al. (1988).

.0318
BETA-ZERO-THALASSEMIA
HBB, TYR35TER

See Fucharoen et al. (1989).

.0319
HEMOGLOBIN HOUSTON
BETA-PLUS-THALASSEMIA, DOMINANT;;
BETA-HOUSTON-THALASSEMIA
HBB, GLN127PRO

In a person of British extraction, Kazazian et al. (1989) found a
gln127-to-pro mutation as the basis of a 'dominant' form of
beta-plus-thalassemia (613985). This form of thalassemia is due to
instability of the beta-globin chains containing the particular
mutation. Kazazian et al. (1992) again reported on the CAG-CGG missense
mutation at codon 127 which caused thalassemia intermedia with hemolysis
in 3 generations of a British-American family. They commented that the
paucity of high-frequency exon 3 mutations and the worldwide
distribution of the few that are observed are probably attributable to
their phenotypic severity and lack of increased genetic fitness in
relation to malaria.

.0320
BETA-PLUS-THALASSEMIA
HBB, GLN127PRO AND ALA128DEL

In a Japanese patient with beta-plus-thalassemia (613985), Hattori et
al. (1989) found deletion of nucleotides AGG from codons 127 and 128
(CAG to GCT) resulting in replacement of gln127 and ala128 by proline
(CCT).

.0321
BETA-PLUS-THALASSEMIA
HEMOGLOBIN CAGLIARI
HBB, VAL60GLU

In an Italian with beta-plus-thalassemia (613985), Podda et al. (1989,
1991) found a val60-to-glu substitution.

.0322
BETA-ZERO-THALASSEMIA
HBB, LYS8FS

A frameshift mutation, -AA in codon 8, AAG to G, in the HBB gene was
found in a Turkish patient with beta-zero-thalassemia (613985) by Orkin
and Goff (1981). This mutation was also found in homozygous state in DNA
from the archeologic remains of a child with severe bone pathology
consistent with thalassemia (Filon et al., 1995). The remains came from
a grave thought to date to the Ottoman period, sometime between the 16th
and 19th centuries. From the tooth development, it was estimated that
the child died at the age of about 8 years, whereas patients with this
mutation would be expected to be transfusion-dependent from early
infancy. Filon et al. (1995) also found a rare DNA polymorphism: a
C-to-T transition in the second codon of the HBB gene that did not alter
the corresponding amino acid. This polymorphism is found in 13% of
present-day Mediterranean beta-thalassemia chromosomes and is part of a
haplotype (haplotype IV) that is associated with relatively high levels
of fetal hemoglobin. The disease may have run a milder course because of
linkage to haplotype IV.

.0323
BETA-ZERO-THALASSEMIA
HBB, GLY16FS

A frameshift mutation, -C, codon 16, GGC to GG, in the HBB gene was
found in Asian Indians with beta-zero-thalassemia (613985) by Kazazian
et al. (1984).

.0324
BETA-ZERO-THALASSEMIA
HBB, SER44FS

Frameshift, -C, codon 44, TCC to TC, was found in a Kurdish patient with
beta-zero-thalassemia (613985) by Kinniburgh et al. (1982).

.0325
BETA-ZERO-THALASSEMIA
HBB, 1-BP INS, G, CODONS 8/9

Frameshift, +G, codons 8/9, AAGTCT to AAGGTCT was found in an Asian
Indian with beta-zero-thalassemia (613985) by Kazazian et al. (1984).

.0326
BETA-ZERO-THALASSEMIA
HBB, 4-BP DEL, 41/42CTTT

Frameshift, -4, codons 41/42, TTCTTT to TT, was found in an Asian Indian
with beta-zero-thalassemia (613985) by Kazazian et al. (1984) and in
Chinese by Kimura et al. (1983).

Lau et al. (1997) found that the deletion of CTTT at codons 41/42
accounted for 40% of all beta-thalassemia alleles in Hong Kong. Chiu et
al. (2002) designed allele-specific primers and a fluorescent probe for
detection of this mutation in the HBB gene from maternal plasma by
real-time PCR. Using this method, they showed that beta-thalassemia
major could be excluded from fetal inheritance by demonstrating absence
of inheritance of the paternally transmitted mutation. By studying
circulating fetal DNA in the maternal plasma for this mutation, Chiu et
al. (2002) added beta-thalassemia to the list of disorders that could be
prenatally diagnosed using this noninvasive method, which had previously
demonstrated usefulness in diagnosing sex-linked diseases (Costa et al.,
2002) and fetal rhesus D status (Lo et al., 1998).

.0327
BETA-ZERO-THALASSEMIA
HBB, GLU6FS

Frameshift, -A, codon 6, GAG to GG, was found in Mediterranean patients
by Kazazian et al. (1983). Bouhass et al. (1990) found the same mutation
in an Algerian patient who was a genetic compound. Rosatelli et al.
(1992) found that this mutation accounted for 2.1% of mutations carried
by 3,000 beta-thalassemia chromosomes from the Sardinian population.
Romey et al. (1993) described an improved procedure that allows the
detection of single basepair deletions on nondenaturing polyacrylamide
gels and demonstrated its applicability for identifying this mutation.

.0328
BETA-ZERO-THALASSEMIA
HBB, PHE71FS

Frameshift, +A, codons 71/72, TTAGT to TTTAAGT, was found in Chinese by
Cheng et al. (1984).

.0329
BETA-ZERO-THALASSEMIA
HBB, LEU106FS

Frameshift, +G, codons 106/107, CTGGGC to CTGGGGG, was found in American
blacks by Wong et al. (1987).

.0330
BETA-ZERO-THALASSEMIA
HBB, ALA76FS

Frameshift, -C, codon 76, GCT to GT, was found in an Italian by DiMarzo
et al. (1988). Rosatelli et al. (1992) found that this mutation was
responsible for 0.7% of the mutations carried by 3,000 beta-thalassemia
chromosomes in the Sardinian population.

.0331
BETA-ZERO-THALASSEMIA
HBB, TRP37FS

Frameshift, -G, codon 37, TGG to G, was found in a Kurdish patient by
Rund et al. (1989, 1991).

.0332
BETA-ZERO-THALASSEMIA
HBB, PRO5FS

Frameshift, -CT, codon 5, CCT to CC, was found in a Mediterranean
patient by Kollia et al. (1989).

.0333
BETA-ZERO-THALASSEMIA
HBB, VAL11FS

Frameshift, -T, codon 11, GTT to GT, was found in a Mexican patient by
Economou et al. (1990).

.0334
BETA-ZERO-THALASSEMIA
HBB, TYR35FS

Frameshift, -C, codon 35, TAC to TA, was found in Indonesia by Yang et
al. (1989).

.0335
BETA-ZERO-THALASSEMIA
HEMOGLOBIN GENEVA
HBB, ASP114FS

Frameshift, -CT, codon 114, CTG to G, was found in a French patient by
Beris et al. (1988). Hb Geneva is an unstable hemoglobin producing a
hemolytic anemia with inclusion bodies in the peripheral blood after
splenectomy. Heterozygotes show manifestations of a thalassemia-like
disorder.

.0336
BETA-ZERO-THALASSEMIA
HBB, LEU14FS

Frameshift, +G, codon 14/15, CTGTGG to CTGGTGG, was found in Chinese by
Chan et al. (1988).

.0337
BETA-ZERO-THALASSEMIA
HBB, TRP37FS

Frameshift, -7 nucleotides from codons 37-39, TGGACCCAG, was found in a
Turkish patient by Schnee et al. (1989).

.0338
BETA-ZERO-THALASSEMIA
HBB, ASP94FS

Frameshift, +TG, codon 94 (GAC), was found in a Mediterranean patient by
Pirastu et al. (1990).

.0339
BETA-ZERO-THALASSEMIA
HBB, GLY64FS

Frameshift, -G, codon 64, GGC to GC, was found in a Swiss woman
heterozygous for beta-thalassemia by Chehab et al. (1989). This was a
spontaneous mutation as originally described by Tonz et al. (1973). The
father was 45 years old when the proband was born. By haplotyping,
Chehab et al. (1989) showed, furthermore, that the mutation had arisen
on the father's chromosome 11.

.0340
BETA-ZERO-THALASSEMIA
HBB, VAL109FS

Frameshift, -G, codon 109, GTG to TG, found in a Lithuanian by Kazazian
et al. (1989).

.0341
BETA-ZERO-THALASSEMIA
HBB, PRO36FS

Frameshift, -T, codon 36/37, CCTTGG to CCTGG, was found in Iranian Kurds
by Rund et al. (1989, 1991).

.0342
BETA-ZERO-THALASSEMIA
HBB, ALA27FS

Frameshift, +C, codons 27/28, GCCCTG to GCCCCTG, was found in Chinese by
Cai et al. (1989).

.0343
BETA-ZERO-THALASSEMIA
HBB, PHE71FS

Frameshift, +T, codon 71, TTT to TTTT, was found in Chinese by Kazazian
(1990).

.0344
BETA-ZERO-THALASSEMIA
HBB, MET1ARG

This initiator codon mutant, ATG to AGG, was found in Chinese
individuals by Kazazian (1990).

.0345
BETA-ZERO-THALASSEMIA
BETA-THALASSEMIA, LERMONTOV TYPE
HBB, MET1THR

This initiator codon mutant, ATG to ACG, was found in Yugoslavians with
beta-zero-thalassemia (613985) by Jankovic et al. (1989). The same
mutation was found by Beris et al. (1993) in a father and daughter of a
family originating from Bern, Switzerland. Unlike the first reported
family, of Yugoslavian origin, the Swiss patients had high Hb F levels.
The mutation converted the initiator methionine to threonine and
abolished an NcoI recognition site.

(In the case of many other genes in which the mutations have been
characterized on the basis of the gene itself, the codon count begins
with the initiator methionine. In such a system, this mutation would be
designated met1-to-thr and the hemoglobin S mutation would be designated
glu7-to-val.)

Molchanova et al. (1998) characterized the beta-thalassemia present in 3
generations of a branch of the family of the Russian poet Mihail
Yurievich Lermontov. The hematologic data for affected members of 3
generations were compatible with a beta-thal heterozygosity. Sequence
analysis showed an ATG-to-ACG change in the initiation codon. The family
in which it was first observed by Jankovic et al. (1989, 1990) was said
to have been of Croatian origin. In that family, the mutation was
accompanied by a CAC-to-CAT change in codon 2 of the same chromosome;
this common polymorphism was not seen in the Russian family.

.0346
BETA-ZERO-THALASSEMIA
HBB, IVS1, G-A, +1

Splice junction mutant, G to A, position 1 of IVS1, was found by Orkin
et al. (1982) in a Mediterranean patient.

.0347
BETA-ZERO-THALASSEMIA
HBB, IVS1, G-T, +1

Splice junction mutant, G to T, at position 1 of IVS1 was found in an
Asian Indian and in Chinese by Kazazian et al. (1984).

.0348
BETA-ZERO-THALASSEMIA
HBB, IVS2, G-A, +1

A splice junction mutant, G to A, at position 1 of IVS2 was found in a
Mediterranean by Treisman et al. (1982), in a Tunisian by Chibani et al.
(1988), and in an American black by Thein et al. (1988). The same
mutation was found by Hattori et al. (1992), who referred to the
mutation as IVS2-1 (G-A).

This is one of the earliest mutations at a 5-prime splice site to be
described. In an analysis of 101 different examples of point mutations
that lie in the vicinity of mRNA splice junctions and that have been
held to be responsible for human genetic disease by altering the
accuracy or efficiency of mRNA splicing, Krawczak et al. (1992) found
that 62 were located at 5-prime splice sites, 26 at 3-prime splice
sites, and 13 resulted in the creation of novel splice sites. They
estimated that up to 15% of all point mutations causing human genetic
disease result in an mRNA splicing defect. Of the 5-prime splice site
mutations, 60% involve the invariant GT dinucleotides.

Sierakowska et al. (1996) found that treatment of mammalian cells stably
expressing the IVS2-654 beta HBB gene with antisense oligonucleotides
targeted at the aberrant splice sites restored correct splicing in a
dose-dependent fashion, generating correct human beta-globin mRNA and
polypeptide. Both products persisted for up to 72 hours after treatment.
The oligonucleotides modified splicing by a true antisense mechanism
without overt unspecific effects on cell growth and splicing of other
pre-mRNAs. Sierakowska et al. (1996) stated that this novel approach in
which antisense oligonucleotides are used to restore rather than to
downregulate the activity of the target gene is applicable to other
splicing mutants and is of potential clinical interest.

This mutation is frequent among patients in southern China and Thailand,
accounting for 20% of beta-thalassemia in some regions. It causes
aberrant RNA splicing. Lewis et al. (1998) modeled this mutation in
mice, replacing the 2 (cis) murine adult beta-globin genes with a single
copy of the human mutant HBB gene. No homozygous mice survived
postnatally. Heterozygous mice carrying this mutant gene produced
reduced amounts of mouse beta-globin chains and no human beta globin,
and had a moderately severe form of beta-thalassemia. Heterozygotes
showed the same aberrant splicing as their human counterparts and
provided an animal model for testing therapies that correct splicing
defects at either the RNA or DNA level.

.0349
BETA-ZERO-THALASSEMIA
HBB, IVS1, T-G, +2

Splice junction mutant, T to G, at position 2 of IVS1 was found in a
Tunisian by Chibani et al. (1988).

.0350
BETA-ZERO-THALASSEMIA
HBB, IVS2, T-C, +2

Splice junction mutant, T to C, at position 2 of IVS1 was found in an
American black by Gonzalez-Redondo et al. (1989). Of 33 thalassemic
chromosomes in Algerian patients studied by Bouhass et al. (1990), 7
carried the T-to-C transition at position 2 in IVS1. Thus, the mutation
may be common in the Algerian population. They observed 2 patients who
were homozygous for the substitution and had no detectable Hb A by
standard electrophoresis procedures. Interestingly, the other 2 possible
changes at this position have also been observed; see 141900.0349 and
141900.0392.

.0351
BETA-ZERO-THALASSEMIA
HBB, IVS1, 17-BP DEL

Deletion of 17 nucleotides that removed the acceptor splice site from
IVS1 was found in a Kuwaiti by Kazazian and Boehm (1988).

.0352
BETA-ZERO-THALASSEMIA
HBB, IVS1, 25-BP DEL

Deletion of 25 nucleotides that removed the acceptor splice site of IVS1
was found in an Asian Indian by Orkin et al. (1983).

.0353
BETA-ZERO-THALASSEMIA
HBB, IVS2, A-G, -2

Change from CCACAGC to CCACGGC (A to G at position -2) in the acceptor
splice site of IVS2 was found in American blacks by Antonarakis et al.
(1984) and Atweh et al. (1985).

This is one of the earliest-described examples of mutation in the
3-prime splice site affecting mRNA splicing. In an analysis of 101
different examples of point mutations occurring in the vicinity of mRNA
splice junctions and resulting in human genetic disease, Krawczak et al.
(1992) found that 26 involved 3-prime splice sites.

.0354
BETA-ZERO-THALASSEMIA
HBB, IVS2, A-C, -2

Change from CCACAGC to CCACCGC (A to C at position -2) at acceptor
splice site of IVS2 was found in American blacks by Padanilam and
Huisman (1986).

.0355
BETA-ZERO-THALASSEMIA
HBB, IVS1, 44-BP, SS DEL

Deletion of 44 nucleotides that removed the IVS1 donor splice site was
found in a Mediterranean patient by Kazazian and Boehm (1988).

.0356
BETA-ZERO-THALASSEMIA
HBB, IVS1, G-A, -1

In an Egyptian child with thalassemia major, Deidda et al. (1990) found
heterozygosity for a G-to-A substitution at position -1 of IVS1, which
altered the conserved dinucleotide AG present in the consensus acceptor
sequence. The other chromosome carried the T-to-C mutation at position 6
of the first intervening sequence (IVS1) (141900.0360). The latter
mutation was associated with haplotype 6, frequently observed in
Mediterranean areas; the new mutation was associated with haplotype 1.
This gene can be added to the list of mutations that can be identified
by Southern analysis using AflII.

.0357
BETA-PLUS-THALASSEMIA
HBB, IVS1, G-C, +5

A G-to-C change at position 5 of the donor site consensus sequence of
IVS1 (CAG-GTTGGT to CAG-GTTGCT) was found in an Asian Indian with
beta-plus-thalassemia (613985) by Kazazian et al. (1984) and in a
Chinese with the same disorder by Cheng et al. (1984).

.0358
BETA-PLUS-THALASSEMIA
HBB, IVS1, G-T, +5

This mutation is a cause of beta-plus-thalassemia (613985). A G-to-T
change at position 5 of the donor site consensus sequence of IVS1
(CAG-gttggt-to-CAG-gttgtt) was found in a Mediterranean patient and an
Anglo-Saxon patient by Atweh et al. (1987) and in an American black by
Gonzalez-Redondo et al. (1988). The 2 cases of Atweh et al. (1987) were
in different RFLP backgrounds, suggesting that they represented
independent mutations. Atweh et al. (1987) showed that after transfer of
the cloned genes into HeLa cells, followed by transient expression,
partial inactivation of the normal donor splice site of IVS1 and
activation of 2 major and 1 minor cryptic splice sites occur. The
effects of this mutation on mRNA splicing were similar to those of
another beta-thalassemia gene with a G-to-C transition at the same
position (141900.0357). In a rare case of beta-thalassemia in a German
family, Eigel et al. (1989) found a G-to-T transversion at the intron 1
donor site of the beta-globin gene. This may be the same mutation. The
patient was homozygous for this mutation and had died at age 27 of heart
failure resulting from iron overload.

.0359
BETA-PLUS-THALASSEMIA
HBB, IVS1, G-A, +5

A G-to-A change at position 5 of the donor site consensus sequence of
IVS1 (CAG-GTTGGT to CAGGTTGAT) was found in an Algerian patient with
beta-plus-thalassemia (613985) by Lapoumeroulie et al. (1986).

.0360
BETA-PLUS-THALASSEMIA
HBB, IVS1, T-C, +6

T-to-C change at position 6 of the donor site consensus sequence of IVS1
(CAG-GTTGGT to CAG-GTTGGC) was found in a Mediterranean patient by Orkin
et al. (1982).

.0361
BETA-PLUS-THALASSEMIA
HBB, IVS2, C-A, -3

A C-to-A change at position -3 in the acceptor splice site of IVS2 (CAG
to AAG) was found in an Iranian, an Egyptian, and an American black by
Gonzalez-Redondo et al. (1988) and Wong et al. (1989).

.0362
BETA-PLUS-THALASSEMIA
HBB, IVS1, T-G, -3

A T-to-G change at position -3 in the acceptor splice site of IVS1 (TAG
to GAG) was found in a Saudi Arabian patient with beta-plus-thalassemia
(613985) by Wong et al. (1989). Indeed, Wong et al. (1989) identified 2
different nucleotide substitutions in consensus acceptor splice
sequences of the beta-globin gene leading to beta-thalassemia. One was
at the IVS1/exon 2 junction and the other at the IVS2/exon 3 junction
(141900.0361). Both mutations were single nucleotide substitutions,
T-to-G and C-to-A, at position -3 immediately adjacent to the invariant
AG dinucleotide. For the IVS2/exon 3 mutation, abnormal splicing into
the cryptic splice site at IVS2 nucleotide 579 was demonstrated.

.0363
BETA-PLUS-THALASSEMIA
HBB, IVS1, C-A, -8

A C-to-A change at position -8 in the acceptor splice site of IVS2 was
found in an Algerian patient with beta-plus-thalassemia (613985) by
Beldjord et al. (1988).

.0364
BETA-PLUS-THALASSEMIA
HBB, IVS1, G-A, +110

A G-to-A change at position 110 of IVS1 was found in a Mediterranean
patient with beta-thalassemia (613985) by Spritz et al. (1981) and
Westaway and Williamson (1981). The mutation created a new splice
acceptor site.

Kaplan et al. (1990) studied the molecular basis of beta-thalassemia
minor, which has a frequency of about 1% among French Canadians residing
in Portneuf County of Quebec Province. They showed that there were 2
different beta-thalassemia mutations segregating in the population: an
RNA processing mutation involving nucleotide 110 of IVS1 on haplotype 1
and a point mutation leading to chain termination through a nonsense
codon at position 39 (141900.0312), occurring on haplotype 2.

.0365
BETA-ZERO-THALASSEMIA
HBB, IVS1, T-G, +16

A T-to-G change at position 16 of IVS1 was found in a Mediterranean
patient by Metherall et al. (1986). The mutation created a new acceptor
splice site.

.0366
BETA-PLUS-THALASSEMIA
HBB, IVS2, T-G, +705

A T-to-G change at position 705 of IVS2 was found in a Mediterranean
patient with beta-plus-thalassemia (613985) by Dobkin et al. (1983). The
mutation created a new acceptor splice site.

.0367
BETA-PLUS-THALASSEMIA
HBB, IVS2, C-G, +745

A C-to-G change at position 745 of IVS2 was found in a Mediterranean
patient with beta-plus-thalassemia (613985) by Orkin et al. (1982). The
mutation created a new acceptor splice site.

.0368
BETA-ZERO-THALASSEMIA
HBB, IVS2, C-T, +654

A C-to-T change at position 654 of IVS2 was found in a Chinese by Cheng
et al. (1984).

.0369
BETA-PLUS-THALASSEMIA
HBB, GGT24GGA AND GLY24GLY

In an American black patient with beta-plus-thalassemia (613985),
Goldsmith et al. (1983) found a change in codon 24 from GGT to GGA.
Although silent in terms of changing the amino acid sequence, the
mutation affected processing of mRNA.

.0370
BETA-PLUS-THALASSEMIA
HBB, -101C-T

Gonzalez-Redondo et al. (1989) found a C-to-T change in nucleotide -101
in an asymptomatic Turkish carrier of beta-thalassemia. This is one of
the transcriptional mutants causing beta-thalassemia. Ristaldi et al.
(1990) showed that this mutation is a relatively frequent cause of
beta-thalassemia in the Italian population, where it is always
associated with haplotype 1. Compound heterozygosity for this promoter
mutation and a mutation for severe beta-thalassemia results in a mild
form of thalassemia intermedia (Murru et al., 1991). In studies of
infants of Italian couples, 1 member of which was heterozygous for this
promoter mutation, Murru et al. (1993) demonstrated that mutation leads
to a more severe defect in beta-globin chain production in infancy than
in adulthood. The moment of transition from the fetal-infant to the
adult pattern of expression seems to be at about 2 years of age. This
age-related pattern of expression had not been detected for other
beta-thalassemia mutations. Assuming the existence of different distal
CACCC box binding proteins with an activating function on the
beta-globin gene promoter in fetal and adult ages, Murru et al. (1993)
speculated that the fetal type interacts less efficiently with the
mutated CACCC promoter as compared with the adult one. They suggested
that the findings permit one to predict a mild phenotype even when HbA
is absent in the newborn.

Maragoudaki et al. (1999) reported the clinical, hematologic,
biosynthetic, and molecular data on 25 double heterozygote
beta-thalassemia intermedia patients and 45 beta-thalassemia
heterozygotes with the C-to-T substitution at nucleotide position -101
from the cap site, in the distal CACCC box of the HBB promoter. This
mutation is considered the most common among the silent beta-thalassemia
mutations in Mediterranean populations. Of the 25 compound heterozygotes
for the promoter mutation and common severe beta-thalassemia mutations,
all but 1 had mild thalassemia intermedia preserving hemoglobin levels
around 9.5 g/dl and hemoglobin F levels less than 25%. Strict assessment
of hematologic and biosynthetic findings in the heterozygotes for the
promoter mutation demonstrated that less than half of them had
completely normal (silent) hematology.

.0371
BETA-PLUS-THALASSEMIA
HBB, -92C-T

Kazazian (1990) found a C-to-T change at position -92 in a Mediterranean
patient with beta-plus-thalassemia (613985).

.0372
BETA-PLUS-THALASSEMIA
HBB, -88C-T

Orkin et al. (1984) found a C-to-T change at position -88 in an American
black and an Asiatic Indian with beta-plus-thalassemia (613985).

.0373
BETA-PLUS-THALASSEMIA
HBB, -88C-A

In a Kurdish Jew with beta-plus-thalassemia (613985), Rund et al. (1989,
1991) found a C-to-A change at position -88.

.0374
BETA-PLUS-THALASSEMIA
HBB, -87C-G

In a Mediterranean patient with beta-plus-thalassemia (613985), Orkin et
al. (1982) found a C-to-G change at position -87.

.0375
BETA-PLUS-THALASSEMIA
HBB, -86C-G

In a Lebanese patient with beta-plus-thalassemia (613985), Kazazian
(1990) found a C-to-G change at position -86.

.0376
BETA-PLUS-THALASSEMIA
HBB, -31A-G

In a Japanese patient with beta-plus-thalassemia (613985), Takihara et
al. (1986) found an A-to-G change at position -31. Also see Yamashiro et
al. (1989).

.0377
BETA-PLUS-THALASSEMIA
HBB, -30T-A

In a Turkish patient with beta-plus-thalassemia (613985), Fei et al.
(1988) found a T-to-A change at position -30 (a TATA box mutation).
Fedorov et al. (1992) found the T-30A mutation in a Karachai patient
with beta-thalassemia intermedia.

.0378
BETA-PLUS-THALASSEMIA
HBB, -30T-C

In a Chinese with beta-plus-thalassemia (613985), Cai et al. (1989)
demonstrated a new beta-thalassemia mutation: a T-to-C mutation at
position -30 converting a normal TATA box sequence from ATAAA to ACAAA.

.0379
BETA-PLUS-THALASSEMIA
HBB, -29A-G

An A-to-G change at position -29 (a TATA box mutation) was found in an
American black by Antonarakis et al. (1984) and in a Chinese patient
with beta-plus-thalassemia (613985) by Huang et al. (1986).

.0380
BETA-PLUS-THALASSEMIA
HBB, -28A-C

In a Kurdish Jew with beta-plus-thalassemia (613985), Poncz et al.
(1983) found an A-to-C change at position -28 (a TATA box mutation).

.0381
BETA-PLUS-THALASSEMIA
HBB, -28A-G

In Chinese patient with beta-plus-thalassemia, Orkin et al. (1983) found
an A-to-G change at position -28 (a TATA box mutation).

.0382
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, T-C, +3

In an American black patient with beta-plus-thalassemia (613985), Orkin
et al. (1985) found a change from AATAAA to AACAAA in the 3-prime
untranslated portion of the gene. This and several others are RNA
cleavage and polyadenylation mutants.

.0383
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, A-G, +6

In a Kurdish patient with beta-plus-thalassemia (613985), Rund et al.
(1989, 1991, 1992) found a change from AATAAA-to-AATAAG in the 3-prime
untranslated portion of the gene. Rund et al. (1992) used this and
another polyadenylation mutation (141900.0417) to investigate the
function of the poly(A) signal in vivo and to evaluate the mechanism
whereby these mutations lead to a thalassemic phenotype. Analysis of RNA
derived from peripheral blood demonstrated the presence of elongated RNA
species in patients carrying either mutation. Other aspects of RNA
processing (initiation, splicing) were unimpaired.

.0384
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, A DEL, +4

In an Arab patient with beta-plus-thalassemia (613985), Kazazian (1990)
found deletion of an A in the 3-prime RNA cleavage-polyadenylation
signal, i.e., a change from AATAAA to AATAA.

.0385
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, G INS, +4

In a Mediterranean patient with beta-plus-thalassemia (613985), Jankovic
et al. (1989) found a change from AATAA to AATGAA in the RNA
cleavage-polyadenylation signal.

.0386
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, A-G, +5

In a Malaysian patient with beta-plus-thalassemia (613985), Jankovic et
al. (1989) found a change from AATAAA to AATAGA in the RNA
cleavage-polyadenylation signal.

.0387
BETA-PLUS-THALASSEMIA
HBB, CAP, A-C

In an Asian Indian patient with beta-plus-thalassemia (613985), Wong et
al. (1986) found a cap site mutation, specifically, an A-to-C change at
position 1. The first nucleotide of the transcript is designated the cap
site; it is usually 60-100 nucleotides 5-prime of the initiator
methionine codon in the untranslated part of the transcript. The cap
site is the nucleotide to which a 7-methyl-G cap is added to the mRNA
transcript. The mutation reported by Wong et al. (1987) is the only cap
site mutation reported to date (Kazazian, 1992).

.0389
HEMOGLOBIN BIRMINGHAM
HBB, 9-BP DEL

Wilson et al. (1990) found loss of leu-ala-his-lys at positions 141,
142, 143, and 144 and their replacement by a gln residue. The changes
were the result of a deletion of 9 nucleotides, namely, 2 bp of codon
141, all of codons 142 and 143, and 1 bp of codon 144; the remaining CAG
triplet (C from codon 141 and AG from codon 144) codes for the inserted
glutamine.

.0390
HEMOGLOBIN GALICIA
HBB, 3-BP DEL

In a Spanish patient, Wilson et al. (1990) found that his and val at
positions 97 and 98 of the beta-chain had been replaced by a leu
residue. The change resulted from the deletion of ACG in codons 97 and
98 and the creation of a remaining triplet CTG (C from codon 97 and TG
from codon 98) which codes for the inserted leucine residue. Wilson et
al. (1990) considered 2 mechanisms, namely, slipped mispairing in the
presence of short repeats, and misreading by DNA polymerase due to a
local distortion of the DNA helix, as the basis for the small deletions
in hemoglobin Birmingham and hemoglobin Galicia.

.0391
HEMOGLOBIN SOUTH MILWAUKEE
HBB, LEU105PHE

In 4 generations of a family of English ancestry, Honig et al. (1990)
found 15 persons with erythrocytosis. Elevated hemoglobin levels were
accompanied by leftward-shifted whole blood oxygen equilibrium curves.
Phlebotomies for relief of symptoms attributable to erythrocytosis had
been necessary in 5 of the affected family members. In the affected
individuals, 43% of the beta chains contained a leucine-to-phenylalanine
substitution at position 105. Oxygen equilibrium curves demonstrated
normal Bohr effect but decreased cooperativity.

.0392
BETA-ZERO-THALASSEMIA
HBB, IVS1, T-A, +2

Bouhass et al. (1990) described an Algerian patient with
beta-zero-thalassemia (613985) who was a genetic compound for the
mutation listed as 141900.0327 and a new mutation consisting of a T-to-A
transversion at position 2 of IVS1.

.0393
HEMOGLOBIN DHONBURI
HEMOGLOBIN NEAPOLIS
HBB, VAL126GLY

While investigating the mechanism of a beta-thalassemia intermedia
phenotype in a 34-year-old Thai male, Bardakdjian-Michau et al. (1990)
discovered a new beta-hemoglobin variant, val126-to-gly, which they
called Hb Dhonburi. The variant was unstable but exhibited normal
oxygen-binding properties. Pagano et al. (1991) found the same amino
acid substitution in 3 unrelated families from southern Italy and dubbed
it Neapolis. A GTG-to-GGG mutation was responsible for the change. The 8
heterozygous patients showed hematologic and biosynthetic alterations of
mild beta-thalassemia. The characteristics were very similar to those of
Hb E (141900.0071), Hb Knossos (141900.0149), and Hb Malay
(141900.0168), all of which have a single base substitution causing
amino acid replacement and alternative splicing of the precursor
beta-mRNA by activating cryptic donor sites in exon 1.

Moghimi et al. (2004) demonstrated this variant in a family from
northern Iran.

.0394
HEMOGLOBIN IOWA
HBB, GLY119ALA

Plaseska et al. (1990) found a gly-to-ala mutation at position beta119
in a black infant and her mother. The baby was also heterozygous for Hb
S (141900.0243). The change in hemoglobin Iowa did not affect stability
or oxygen-carrying properties; hematologic data were normal in the
mother and child.

Somjee et al. (2004) described Hb Iowa in compound heterozygous state,
not with Hb S as in the initial report, but with Hb C (141900.0038). The
patient was an African American girl, originally diagnosed as homozygous
Hb C during neonatal screening. Both cases indicated that there were no
abnormal hematologic manifestations associated with this rare hemoglobin
variant. However, in both cases, Hb Iowa was mistaken for Hb F during
routine neonatal screening. Neonatal misidentification of Hb Iowa led to
misdiagnosis of sickle cell disease in the patient of Plaseska et al.
(1990) and Hb C in the patient of Somjee et al. (2004).

.0395
BETA-THALASSEMIA
HBB, 1-BP INS, A, CODON 47

In a Suriname carrier of beta-thalassemia (613985), Losekoot et al.
(1990) detected a frameshift insertion in the HBB gene: a single
nucleotide (+A) at codon 47 which caused the formation of a termination
codon at position 52.

.0396
HEMOGLOBIN CALAIS
HBB, ALA76PRO

In a 43-year-old woman suffering from chronic anemia since the age of
20, Wajcman et al. (1991) found this new hemoglobin variant which
displays decreased oxygen affinity.

.0397
HEMOGLOBIN ZENGCHENG
HBB, LEU114MET

This variant was detected in a cord blood sample from a Chinese newborn
tested by IEF and reversed phase high performance liquid chromatography
(Plaseska et al., 1990). This mutation occurs with another mutation in
Hb Masuda (141900.0172).

.0398
HEMOGLOBIN TERRE HAUTE
BETA-PLUS-THALASSEMIA
HBB, LEU106ARG

Adams et al. (1978, 1979) described a hemoglobin variant responsible for
severe beta-thalassemia with dominant inheritance. They concluded that
the mutation, which they referred to as Hb Indianapolis (see
141900.0117), carried a cys112-to-arg mutation. Subsequent description
of 2 families, which indeed carried this mutation but were minimally
affected, prompted restudy of the original family. Both of the original
carriers of the variants had succumbed to their severe anemia. However,
by the use of PCR, enough DNA was recovered from a 10-year-old bone
marrow microscope slide to sequence the third exon of the beta-globin
gene. These studies showed substitution of arginine for leucine at
position 106 of the beta-globin chain. In order to avoid confusion with
the cys112-to-arg mutation, to which the name Hb Indianapolis was firmly
attached, Coleman et al. (1991) renamed the original variant hemoglobin
Hb Terre Haute. The dominantly inherited beta-thalassemias that are due
to highly unstable variant beta chains, such as HB Indianapolis, result
from the rapid catabolism of the beta chains and consequent erythroblast
destruction within the bone marrow. These differ from the classic
unstable hemoglobin variants in which most damage occurs to erythrocytes
in the circulation, resulting in hemolytic anemia rather than impaired
erythropoiesis.

.0399
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, A-G, +4

In a Dutch patient with a mild, nontransfusion dependent
beta-thalassemia phenotype (613985), Losekoot et al. (1991) found a
mutation in the cleavage-polyadenylation sequence. The mutation,
AATAAA-to-AATGAA, was detected using denaturing gradient gel
electrophoresis (DGGE) and direct sequencing of genomic DNA amplified by
PCR.

.0400
HEMOGLOBIN VALLETTA
HBB, THR87PRO

Kutlar et al. (1991) described a new hemoglobin variant called Hb
Valletta, which is characterized by a threonine-to-proline substitution
at position 87 of the beta chain. This mutation was found to be linked
to that of the gamma-chain variant Hb F-Malta-I (142250.0014) which has
a his-to-arg mutation at position 117 of the G-gamma chain. The 2 genes
are 27 to 28 kb apart. No chromosomes with one or the other mutation
alone were identified.

.0401
HEMOGLOBIN JACKSONVILLE
HBB, VAL54ASP

In a 12-year-old black male with splenomegaly and anemia, Gaudry et al.
(1990) found a hemoglobin variant manifest by electrophoretic
abnormality. This unstable hemoglobin was found to have a substitution
of aspartic acid for valine at position 54 of the beta chain.

.0402
HEMOGLOBIN CHESTERFIELD
HBB, LEU28ARG

Thein et al. (1991) reported a patient with severe heterozygous
beta-thalassemia characterized by large inclusion bodies and resulting
in a single base substitution, CTG to CGG, in codon 28 in exon 1. The
mutant hemoglobin, called Hb Chesterfield, had an unstable beta chain.
The patient was a 34-year-old English woman who had presented at the age
of 7 years with abdominal pain, anemia, jaundice, and
hepatosplenomegaly. She had been transfusion-dependent since the age of
10. Because of increasing transfusion requirements, a splenectomy was
performed at the age of 13. Cholecystectomy was required at the age of
28.

.0403
HEMOGLOBIN QUEBEC-CHORI
HEMOGLOBIN CHORI
HBB, THR87ILE

Witkowska et al. (1991) found that sickle cell disease in a 3-year-old
girl was due to compound heterozygosity for the Hb S gene and a new
mutation called Hb Quebec-Chori. ('Chori' is an acronym for the
Children's Hospital Oakland Research Institute.) Although the purified
variant had gelling properties similar to those of Hb A, a mixture of it
with Hb S resulted in a delay time of polymerization very similar to
that of a homogeneous solution of Hb S. The sickle gene was inherited
from the father, who was black and originally from Guyana. The new
mutant was inherited from the mother, who was white and of
English-Irish-French Canadian extraction. By peptide analysis, the new
hemoglobin was found to have substitution of isoleucine for
threonine-87.

.0404
HEMOGLOBIN REDONDO
HEMOGLOBIN ISEHARA
HBB, HIS92ASN-TO-ASP

In a Portuguese patient suffering from a chronic hemolytic anemia,
Wajcman et al. (1991) found an unstable hemoglobin which contained a
his92-to-asn substitution. The variant readily loses its heme group and
a rapid deamidation occurs in vitro, yielding an asp92 semihemoglobin.
The oxygen affinity of the patient's red blood cells was increased,
leading to stimulation of erythropoiesis and a macrocytic hemolytic
disease. Harano et al. (1991) found the same unstable hemoglobin variant
in a Japanese female with hemolytic anemia and called it Hb Isehara.

In addition to Hb Redondo, 6 other rare Hb variants had been reported in
which deamidation of an asn residue to an asp occurred as a spontaneous
posttranslational modification: Hb J (Sardegna) (141850.0036), Hb J
(Singapore) (141800.0075), Hb La Roche-sur-Yon (141900.0482), Hb Osler
(141900.0211), Hb Providence (141900.0227), and Hb Wayne (141850.0004).

.0405
HEMOGLOBIN COIMBRA
HBB, ASP99GLU

In a Portuguese family living in Coimbra, Portugal, Tamagnini et al.
(1991) identified a high oxygen affinity hemoglobin variant. Aspartic
acid at residue 99 was replaced by glutamic acid in the beta chain. Two
affected members had erythrocytosis with hemoglobin levels of 18 to 20
g/dl. A GAT-to-GAA mutation at codon 99 represented the seventh type of
substitution at this specific location. From a survey of mutations,
Tamagnini et al. (1991) suggested that codons GAC(asp), GAT(asp),
GAG(glu), and GAA(glu) are particularly susceptible to mutational
events.

.0406
BETA-PLUS-THALASSEMIA
HBB, C-A, -32

Lin et al. (1992) described a mutation in the TATA box that has the
sequence CATAAA and is located about 30 nucleotides upstream of the cap
site. The mutation changed CATAAA to AATAAA.

.0407
HEMOGLOBIN CLEVELAND
HBB, CYS93ARG AND GLU121GLN

See Wilson et al. (1991). This hemoglobin variant combines the mutations
present in Hb D (glu121-to-gln; 141900.0065) and in Hb Okazaki
(cys93-to-arg; 141900.0207).

.0408
HEMOGLOBIN GRENOBLE
HBB, PRO51SER AND ASP52ASN

See Lacombe et al. (1990). The asp52-to-asn mutation is also found in Hb
Osu Christiansborg (141900.0212).

.0409
HEMOGLOBIN KODAIRA
HBB, HIS146GLN

This abnormal hemoglobin was discovered in a 75-year-old Japanese male
with an unusually low level of Hb A(1c) (Harano et al., 1990, 1992). The
patient was being treated for chronic renal failure. A CAC-to-CAA change
in codon 146 was responsible for substitution of glutamine for
histidine. Hb Kodaira was the fifth hemoglobin variant involving the
terminal codon of the beta chain. The others are Hb Hiroshima
(141900.0110), Hb York (141900.0305), Hb Cowtown (141900.0056), and Hb
Cochin-Port Royal (141900.0051).

.0410
HEMOGLOBIN MONTREAL
HBB, 9-BP DEL AND 12-BP INS

Plaseska et al. (1991) described a new variant with a beta chain 1
residue longer than the normal as a result of the deletion of asp, gly,
and leu at positions 73, 74, and 75 and the insertion of ala, arg, cys,
and gln in their place. Hb Montreal is unstable.

.0411
HEMOGLOBIN NIKOSIA
HBB, LYS17GLN

See Spivak (1989).

.0412
HEMOGLOBIN ST. FRANCIS
HBB, GLU121GLY

See Abourzik et al. (1991). This mutation is at the same nucleotide as
that in Hb D (Los Angeles) (141900.0065).

.0413
HEMOGLOBIN YAHATA
HBB, CYS112TYR

See Harano et al. (1991).

.0414
HEMOGLOBIN RANCHO MIRAGE
HBB, HIS143ASP

A variant hemoglobin resulting from substitution of aspartic acid for
histidine at residue 143 of the beta chain was detected in a 17-year-old
male who had mild anemia (Moo-Penn et al., 1992).

.0415
BETA-ZERO-THALASSEMIA
HBB, GLU90TER

In affected members in a Japanese family with beta-zero-thalassemia
(613985), Hattori et al. (1992) found a GAG-to-TAG change in codon 90,
substituting a stop codon for glutamic acid. The mutation had previously
been found only in Japanese, the first case having been reported by
Harano et al. (1989).

.0416
BETA-ZERO-THALASSEMIA
HBB, IVS2AS, -3, C-G

Hattori et al. (1992) identified this mutation in a Japanese patient
with beta-zero-thalassemia (613985). The abnormality was a substitution
of guanine for cytosine at nucleotide 848 of IVS2. This nucleotide is at
position -3 in the acceptor splice sequence. A C-to-A mutation at the
same site in an Iranian patient had been reported by Wong et al. (1989);
see 141900.0362.

.0417
BETA-PLUS-THALASSEMIA
HBB, 3-NT, 5-BP DEL, AATAAA-A

Rund et al. (1992) used a polyadenylation mutation involving the
deletion of 5-bp (AATAAA-to-A-----) and another mutation (141900.0383)
to study the function of the poly(A) signal in vivo and to evaluate the
mechanism whereby polyadenylation mutations lead to a thalassemic
phenotype.

.0418
BETA-ZERO-THALASSEMIA
HBB, IVS1AS, G-C, -1

In a Sicilian subject with beta-zero-thalassemia (613985), Renda et al.
(1992) identified a G-C substitution in the invariant AG dinucleotide at
the acceptor splice site of the first intron. In the same nucleotide, a
G-A substitution is a frequent cause of beta-zero-thalassemia in
Egyptians (see 141900.0356). Although mutations in the invariant GT or
AG dinucleotide splice junctions are known to give rise to
beta-zero-thalassemia, studies were not performed in the specific
patient reported by Renda et al. (1992) to determine that this was in
fact a beta-zero-thalassemia mutation.

.0419
BETA-ZERO-THALASSEMIA
HBB, 1-BP DEL, GTG-TG

In 3 out of 3,000 beta-thalassemia (613985) chromosomes in the Sardinian
population, Rosatelli et al. (1992) found deletion of a single
nucleotide G at codon 1 (GTG-to-TG), which resulted in both a frameshift
and the formation of an in phase termination codon at codon 3. In
addition, sequencing showed at codon 2 of the globin gene a single
nucleotide substitution, C to T, which is a common silent substitution
in the Mediterranean population (Orkin et al., 1982).

.0420
HEMOGLOBIN MUSCAT
HBB, LEU32VAL

In 2 members of an Arabian family from Oman, Ramachandran et al. (1992)
discovered a leu-to-val replacement at position beta-32 by reversed
phase high performance liquid chromatography. In 1 person, it occurred
with Hb S and in the other with Hb A. Although Hb Muscat was slightly
unstable, its presence had no apparent adverse effect on the health of
its carriers.

.0421
HEMOGLOBIN BAB-SAADOUN
HBB, LEU48PRO

In a young Arabian boy living in Tunisia, Molchanova et al. (1992)
detected a leu48-to-pro substitution in the beta chain. Since the
parents did not have the variant, it presumably occurred by spontaneous
mutation. It was thought not to be the cause of hemolytic anemia.

.0422
HEMOGLOBIN MANHATTAN
HBB, 1-BP DEL, -G, CODON 109

As alleles of the HBB gene producing beta-thalassemia were discovered,
it became evident that there is a relative paucity of beta-thalassemia
mutations in exon 3 of HBB even though this exon accounts for about 30%
of the coding region. It appears to be a general rule that 1-bp
frameshift mutations and nonsense mutations early in exon 3 produce a
chronic hemolytic anemia in the heterozygous state. On the other hand,
mutations of this type in exons 1 and 2 in the heterozygous state
produce beta-thalassemia trait with mild phenotypic deviations from the
normal. Kazazian et al. (1992) reported another example of this rule: in
a 78-year-old Lithuanian Ashkenazi Jew with chronic hemolytic anemia,
they demonstrated a -1 frameshift (-G) in codon 109. The globin was
termed beta-Manhattan for the site of residence of the patient.

.0423
BETA-ZERO-THALASSEMIA
HBB, IVS2, G-C, -1

In 4 members of a Yugoslavian family who exhibited severe microcytosis
and hypochromic anemia (613985), Jankovic et al. (1992) found
heterozygosity for a G-C mutation in the last nucleotide of IVS2. This
change of the invariant AG dinucleotide of the acceptor splice site of
intron 2 abolished normal splicing. Two other mutations of the IVS2
acceptor splice site have been identified as causes of beta-zero
thalassemia; see 141900.0353 and 141900.0354.

.0424
BETA-THALASSEMIA INTERMEDIA
HEMOGLOBIN BRESCIA;;
HEMOGLOBIN DURHAM-N.C.
HBB, LEU114PRO

In a family of northern Italian descent (Brescia-Lombardia), Murru et
al. (1992) found that a 14-year-old girl with the clinical phenotype of
severe thalassemia intermedia (613985) had a heterozygous CTG-to-CCG
change at codon 114 resulting in substitution of proline for leucine in
the beta-globin chain. The resulting hemoglobin tetramer was highly
unstable and precipitated to form inclusion bodies in peripheral red
blood cells. The unusually severe phenotype present in this heterozygote
was thought to be explained by the coinheritance of a triple
alpha-globin locus.

In a 29-year-old female of Irish descent with thalassemia-like anemia
during her first pregnancy, deCastro et al. (1992) found no gross
structural alteration on Southern blot analysis of the globin genes but
found an alpha:beta globin chain synthesis ratio of 0.91 (control =
0.94). Because they suspected an unstable hemoglobinopathy and because
many of these disorders are due to point mutations in exon 3 of the
beta-globin chain, they performed PCR-SSCP analysis, which showed an
abnormality. Sequencing demonstrated a T-to-C transition at codon 114
resulting in a leucine-to-proline substitution. They called the
hemoglobin variant Durham-N.C. to distinguish it from hemoglobin Durham,
named for the city in England. The mutation created a novel MspI
restriction site in exon 3 of the HBB gene. DeCastro et al. (1994)
demonstrated that this hemoglobinopathy, like several others within exon
3 of the beta-globin gene, e.g., Hb Showa-Yakushiji (leu110-to-pro;
141900.0262), result in a thalassemic and/or hemolytic phenotype with
moderately severe microcytic anemia inherited as an autosomal dominant.

Kim et al. (2001) described the molecular and hematologic
characteristics of a Korean family with a dominantly inherited
beta-thalassemia. Carriers were characterized by moderate anemia,
hypochromia, microcytosis, elevated Hb A2 and Hb F levels, and
splenomegaly. A CTG (leu) to CCG (pro) change at codon 114 of the HBB
was demonstrated. They referred to the abnormal hemoglobin as Hb
Durham-N.C./Brescia.

.0425
BETA-PLUS-THALASSEMIA
HBB, C-T, -90

In an asymptomatic Portuguese female with beta-plua-thalassemia
(613985), Faustino et al. (1992) found heterozygosity for a C-to-T
transition at position -90 in the proximal CACCC box.

.0426
BETA-THALASSEMIA INTERMEDIA, DOMINANT
HBB, IVS2DS, 2-BP DEL, AG

In a Portuguese family with 'dominant' beta-thalassemia intermedia
(613985), Faustino et al. (1992) found deletion of nucleotides 4 and 5
(AG) in IVS2 of the HBB gene, converting GTGAGT to GTGTCT.

In a 5-generation Portuguese family, Faustino et al. (1998) described an
autosomal dominant form of beta-thalassemia intermedia. Carriers showed
moderate anemia, hypochromia, microcytosis, elevated Hb A2 and Hb F,
splenomegaly, hepatomegaly, and inclusion bodies in peripheral red blood
cells after splenectomy. The molecular basis was found to be deletion of
2 nucleotides, AG, within the 5-prime splice site consensus sequence of
intron 2 of the HBB gene. The fourth and fifth nucleotides in the
sequence GTGAG were deleted. Reticulocyte RNA studies performed by
RT-PCR and primary extension analysis showed 3 abnormally processed
transcripts, which, upon sequencing, were shown to correspond to (1)
skipping of exon 2, and (2) activation of 2 cryptic splice sites
(between codons 59 and 60), and at nucleotide 47 in the second intron.
In vitro translation studies showed that at least 1 of these aberrant
mRNA species is translated into an abnormally elongated peptide whose
cytotoxic properties could, in part, be causing the atypical dominant
mode of inheritance observed in this family. Faustino et al. (1998)
suggested that this elongated beta chain is unable to combine with an
alpha-globin chain to form a functional hemoglobin molecule. Its
degradation would, then, exhaust the proteolytic defense mechanism of
the erythroid precursors, leading to inefficient proteolysis of the free
alpha chains in excess.

.0427
HEMOGLOBIN DUINO
HBB, HIS92PRO AND ARG104SER

Wajcman et al. (1992) demonstrated that Hb Duino, an unstable
hemoglobin, carries 2 point mutations, the his92-to-pro mutation of Hb
Newcastle (141900.0197) and the arg104-to-ser mutation of Hb Camperdown
(141900.0042). Family studies demonstrated that the Hb Newcastle
abnormality was a de novo mutation of a gene already carrying the Hb
Camperdown substitution. One member of the Italian family studied by
Wajcman et al. (1992) had hemolytic anemia.

.0428
HEMOGLOBIN BADEN
HBB, VAL18MET

Divoky et al. (1992) analyzed the hemoglobin of a child of German
descent living in the former German Democratic Republic and exhibiting
typical clinical features of beta-thalassemia intermedia. One of his
chromosomes 11 and 1 of his mother's carried a GTG-to-ATG mutation at
codon 18, resulting in the replacement of a valine residue by a
methionine residue. Called Hb Baden, the newly discovered beta-chain
variant represented only 2 to 3% of the hemoglobin in both the patient
and his mother because of the presence of an IVS1 +5 G-to-C thalassemic
mutation (141900.0357) on the same chromosome. On the other chromosome,
inherited from the father, the boy carried the val126-to-gly mutation of
Hb Dhonburi (141900.0393), which itself is slightly unstable and
associated with mild thalassemic features.

.0429
HEMOGLOBIN GRAZ
HBB, HIS2LEU

Liu et al. (1992) accidentally detected 2 abnormal hemoglobins by cation
exchange high performance liquid chromatography performed with an
automated system designed to quantitate Hb A1c in blood samples from
patients with diabetes mellitus. The variants eluted together with the
fast-moving Hb A1c. One of the variants, found in 4 healthy, apparently
unrelated adults, involved a change from a histidine to a leucine
residue at position 2 of the beta chain. The second variant was
identical to Hb Sherwood Forest (141900.0261).

.0430
BETA-ZERO-THALASSEMIA
HBB, MET1ILE

In a typical beta-thalassemia (613985) carrier of Italian descent, Saba
et al. (1992) demonstrated a G-to-A transition in the initiation codon
of the HBB gene, producing a substitution of isoleucine for methionine.
The absence of the initiation methionine led to defective beta-globin
mRNA translation and probably determined the complete absence of
beta-chain production. Indeed, initiation of translation may have
occurred at the first downstream ATG sequence, which is located at codon
21-22; the resulting out-of-frame reading probably terminates at the new
UGA termination codon at codon 60-61. Initiation codon mutations
previously described in both the alpha (141850.0022) and beta
(141900.0344) globin genes all result in complete inactivation of the
affected globin gene.

In 7 members of 3 generations of a family living in northern Sweden,
Landin et al. (1995) found an initiation codon mutation ATG-to-ATA of
the HBB gene. The mutation changed the initiation codon from methionine
to isoleucine and resulted in a beta-zero-thalassemic phenotype. The
affected family members all presented hematologic findings typical for
the beta-thalassemic trait, with slight anemia, marked microcytosis, and
increased levels of Hb A2. See 141900.0345 for an initiation codon
mutation ATG-to-ACG, which changes methionine to threonine.

.0431
HEMOGLOBIN KARLSKOGA
HBB, ASP21HIS

In the course of quantification of Hb A(1c) in a 48-year-old Swedish
woman, Landin (1993) discovered a variant hemoglobin that comprised
approximately 39% of the total hemoglobin. A study demonstrated a
GAT-to-CAT mutation in codon 21, corresponding to an asp21-to-his
substitution. As predicted from the location of the substitution in the
molecule, it was not associated with any overt hematologic
abnormalities.

.0432
HEMOGLOBIN MUSKEGON
HBB, GLY83ARG

During a routine hematologic evaluation of a 1-year-old boy and his
father, Broxson et al. (1993) found a variant hemoglobin that produced a
band on electrophoresis in the same position as that for sickle
hemoglobin. Screening of other family members showed that the paternal
grandmother and an uncle also had the variant. Amino acid analysis
demonstrated that glycine at position 83 of the beta-globin chain had
been substituted by arginine. This gly83 is an external residue with no
significant inter- or intra-molecular contacts, and mutation at this
residue would not be expected to cause any changes in the functional
properties of the variant.

.0433
HEMOGLOBIN TIGRAYE
HBB, ASP79HIS

In a healthy 36-year-old male of Ethiopian descent with normal
hematologic findings, Molchanova et al. (1993) found a hemoglobin
variant with electrophoretic mobility on cellulose acetate like that of
Hb S. DNA studies demonstrated a GAC-to-CAC transversion leading to an
asp79-to-his amino acid substitution.

Pistidda et al. (2001) identified the same mutation in a Caucasian in
the Sassari district of Sardinia.

.0434
REMOVED FROM DATABASE
.0435
HEMOGLOBIN SARREBOURG
HBB, GLN131ARG

Duwig et al. (1987) found a new unstable hemoglobin in a boy of 9 years
hospitalized for hematuria and diffuse pains. Clinical examination
demonstrated isolated splenomegaly without hepatomegaly or adenopathy.
He was anemic and the variant hemoglobin constituted 30% of total
hemoglobin. Molecular studies revealed a substitution of arginine for
glutamine-131.

.0436
HEMOGLOBIN SAINT NAZAIRE
HBB, PHE103ILE

In 4 apparently unrelated French families, Wajcman et al. (1993) found 5
patients carrying a hemoglobin variant associated with moderate
erythrocytosis. The structural abnormality was a replacement of
phenylalanine-103 by isoleucine. The residue involved was the same as
that in Hb Heathrow (141900.0102), which is a phe103-to-leu
substitution. The increase in oxygen affinity is much lower in Hb Saint
Nazaire than in Hb Heathrow. The replacement of phenylalanine G5, which
is located within the heme pocket, by leucine abolishes several contacts
between heme and globin and leads to an environment of the heme with
similarities to that observed in myoglobin. In contrast, the replacement
of G5 by an isoleucine is likely to introduce less structural
modifications.

.0437
HEMOGLOBIN HRADEC KRALOVE
HEMOGLOBIN HK
HBB, ALA115ASP

In a Czech family, Divoky et al. (1993) found a GCC-to-GAC mutation in
codon 115 of the beta-globin gene as the cause of dominant
beta-thalassemia trait. The variant hemoglobin was markedly unstable. A
mother and daughter, who were heterozygotes, showed moderate anemia,
reticulocytosis, nucleated red cells, target cells, Heinz body
formation, and splenomegaly. Both had marked increase in fetal
hemoglobin synthesis.

.0438
HEMOGLOBIN MANUKAU
HBB, VAL67GLY

Fay et al. (1993) described hemoglobin Manukau in 2 brothers presenting
with nonspherocytic hemolytic anemia who became transfusion-dependent by
6 months of age. The severity of clinical expression seemed to be
modulated by coexisting alpha-thalassemia. The brothers had a Niuean
mother and a New Zealand Maori father. A second unusual feature was a
modification of beta-141 leu, which appeared to be deleted because
posttranslational modification had changed leu-141 to a residue
(probably hydroxyleucine) that was not detected by standard amino acid
analysis and sequencing methods. The same feature occurs in Hb Coventry
(141900.0055).

.0439
HEMOGLOBIN VILLAVERDE
HBB, SER89THR

In a 41-year-old man in Spain with severe erythrocytosis, Wajcman et al.
(1993) found an electrophoretically silent hemoglobin variant with very
high oxygen affinity and markedly reduced cooperativity. The structural
abnormality was determined by mixing normal and abnormal beta chains,
isolating the abnormal tryptic peptide by reversed-phase HPLC, and
sequencing the peptide by mass spectrometry. Serine-89 was replaced by
threonine.

.0440
HEMOGLOBIN HOWICK
HBB, TRP37GLY

During routine hematologic investigation of a 44-year-old man, Owen et
al. (1993) found a novel hemoglobin with high oxygen affinity and a
substitution of glycine for tryptophan-37. This change would be expected
to result in a destabilization of the deoxyhemoglobin form because of
the reduced number of hydrogen bonds, salt bridges, and van der Waal
contacts between the alpha-1 and beta-2 chains. Hemoglobin was 16.3
g/dL. The variant constituted 29% of the hemoglobin, indicating either
reduced stability of the nascent Hb Howick chain or an impaired
expression level.

.0441
HEMOGLOBIN DENVER
HBB, PHE41SER

Stabler et al. (1994) reported a 16-year-old white boy from Denver,
Colorado, in whom cyanosis of the skin, lips, mucous membranes,
conjunctivas, and nail beds was noted at the time of a dental
extraction. The mother also had lifelong cyanosis and, although
asymptomatic, had had severe anemia during pregnancy. The maternal
grandmother and maternal aunt had chronic cyanosis and mild anemia. No
abnormal hemoglobin band separate from that of hemoglobin A was found on
electrophoresis, HPLC, and isoelectric focusing. However, a heat test
showed hemoglobin instability, and O2 studies disclosed an appreciably
right-shifted dissociation curve. On chromatography, the new
variant--hemoglobin Denver--was found to carry a substitution of serine
for phenylalanine at position 41 in the beta chain. In addition to
reduction in O2 affinity, hemoglobin Denver was accompanied by moderate
reticulocytosis and mild anemia. The corresponding substitution in the
hemoglobin gamma gene is found in hemoglobin F (Cincinnati) (HBG2;
142250.0041) and is associated with cyanosis.

.0442
HEMOGLOBIN BECKMAN
HBB, ALA135GLU

Rahbar et al. (1991) discovered Hb Beckman, an alanine-to-glutamic acid
mutation at position 135 of the HBB gene, in a 32-year-old African
American woman with chronic anemia and microcytosis and a palpable
spleen. While substitution of proline at position 135 (Hb Altdorf;
141900.0007) results in an unstable hemoglobin variant with increased
affinity for oxygen, substitution of glutamic acid has a reverse effect,
i.e., Hb Beckman has reduced oxygen affinity.

.0443
HEMOGLOBIN KOREA
HBB, VAL33DEL OR VAL34DEL

A de novo mutation was reported by Park et al. (1991) in an 8-year-old
boy who presented with symptoms of mild anemia and was found to be
icteric with moderate splenomegaly. PCR followed by DNA sequencing of
the HBB gene demonstrated that the mutation results in a deletion of
valine (GGT) at amino acid position 33 or 34 without altering the
reading frame in the remainder of the subunit. The deletion appears to
disrupt the globin structure badly, producing a clinical phenotype of
beta-thalassaemia resembling that of an ineffective erythropoiesis.

.0444
MOVED TO 141900.0452
.0445
HEMOGLOBIN D (NEATH)
HBB, GLU121ALA

During the course of a genetic survey of the first-year students at a
London Medical School, Hb D (Neath) was discovered in an 18-year-old
Caucasian female by Welch and Bateman (1993). In the variant HBB chain,
the glutamic acid residue at position 121 is replaced with alanine.

.0446
HEMOGLOBIN WASHTENAW
HBB, VAL11PHE

Krishnan et al. (1993, 1994) reported a val-to-phe mutation at position
11 of the HBB chain in 6 members in 3 generations of a family of
Hungarian-American descent. The proband had primary pulmonary
hypertension, and other members of the family were mildly anemic. At
least one other Hb variant, Hb Warsaw (141900.0257), has been reported
to be associated with pulmonary hypertension. Hb Washtenaw is slightly
unstable and has a low oxygen affinity.

.0447
HEMOGLOBIN ALESHA
HBB, VAL67MET

Molchanova et al. (1993) discovered Hb Alesha in a 15-year-old Russian
patient with severe hemolytic disease, anemia, splenomegaly, Heinz body
formation, and continued requirement for blood transfusions despite a
splenectomy at age 3. PCR amplification and sequence analysis of the
hemoglobin beta gene indicated a GTG-to-ATG point mutation at codon 67,
causing a valine-to-methionine transition. Molchanova et al. (1993)
postulated that the replacement of valine by the larger methionyl
residue significantly reduces the stability of the hemoglobin molecule
by disrupting the apolar bonds between the valine and the heme group.

.0448
HEMOGLOBIN DIEPPE
HBB, GLN127ARG

Girodon et al. (1992) reported Hb Dieppe in a 31-year-old French female
with chronic anemia. DNA sequencing revealed a missense mutation
(GAG-to-CGG) at position 127 of the beta-globin gene, causing a
glutamine-to-arginine transition. The hemoglobin variant is highly
unstable; the introduction of a positively charged hydrophilic residue
at position 127 disrupts the tight contacts between the alpha and beta
subunits.

.0449
HEMOGLOBIN HIGASHITOCHIGI
HEMOGLOBIN HT
HBB, GLY24DEL OR GLY25DEL

Hb Higashitochigi was discovered by Fujisawa et al. (1993) in a
2-year-old Japanese boy with chronic cyanosis. The variant is missing a
glycine residue, due to a deletion of 3 nucleotides in the genomic DNA
(codons 24-25: GGTGGT-to-GGT). It is likely that the absence of glycine
indirectly distorts the heme pocket, causing decreased oxygen binding of
the beta chain and impaired oxygen release of the normal alpha chain in
the tetrameric molecule.

.0450
HEMOGLOBIN TROLLHAETTAN
HBB, VAL20GLU

Landin et al. (1994) added another example to the more than 40
hemoglobin variants with increased oxygen affinity associated with
erythrocytosis. In 3 generations of the family of a 23-year-old male
from Trollhaettan in Sweden, Landin et al. (1994) observed
heterozygosity for a GTG-to-GAG transition at codon 20 that predicted a
val-to-glu substitution, which was confirmed at the protein level. The
mutation occurred in the same codon as hemoglobin Olympia (141900.0210),
which shows a val20-to-met amino acid substitution.

.0451
HEMOGLOBIN TYNE
HBB, PRO5SER

In a variant hemoglobin designated Hb Tyne, Langdown et al. (1994)
observed a CCT-to-TCT change in codon 5 predicting substitution of
serine for proline. The variant was first found in a 66-year-old
diabetic male after an inappropriately low level of glycosylated
hemoglobin was detected by enzyme immunoassay, and confirmatory ion
exchange high performance liquid chromatography revealed the presence of
an abnormal hemoglobin. Consequently, Langdown et al. (1994) identified
the same mutation in an apparently unrelated diabetic male. Neither
occurrence of the variant was associated with any abnormal hematologic
findings.

.0452
HEMOGLOBIN MEDICINE LAKE
HBB, VAL98MET AND LEU32GLN

Coleman et al. (1993, 1995) investigated the molecular basis of
transfusion-dependent hemolytic anemia in a Caucasian female infant who
rapidly developed the phenotype of beta-thalassemia major. Both the
father and mother were normal hematologically. The DNA sequence of one
HBB allele demonstrated 2 mutations, one for the moderately unstable Hb
Koln (141900.0151) and another for a novel leu32-to-gln change resulting
from a CTG to CAG transversion. The new hemoglobin was called Hb
Medicine Lake. The hydrophilic gln32 has an uncharged polar side chain
that may distort the B helix and provoke further molecular instability.
Biosynthesis studies of this mutation showed a deficit of beta-globin
synthesis with early loss of beta-globin chains. Coleman et al. (1995)
pointed to 14 previously described hemoglobin variants with 2 mutations
in the same polypeptide chain. Most of these rare disorders had probably
arisen via homologous crossing over. Such a mechanism, however, could
not account for the Hb Medicine Lake, since neither parent had a
detectable abnormal hemoglobin gene. Therefore, it was presumed that
this was a true double de novo mutation.

.0453
HEMOGLOBIN YAIZU
HBB, ASP79ASN

Harano et al. (1995) used the designation Hb Yaizu, after the city where
the carrier lived, for a new beta-chain variant found in a Japanese
female who was apparently healthy. Isoelectric focusing showed an
abnormal hemoglobin band between the normal A2 and A bands. An
asp79-to-asn amino acid substitution was demonstrated.

.0454
BETA-ZERO-THALASSEMIA
HBB, IVS2AS, G-A, -1

Curuk et al. (1995) described an American family of English-Scottish
descent in which 6 members were found to be heterozygous for
beta-thalassemia (613985). Sequencing of the HBB gene showed a G-to-A
transition at the splice acceptor site of the second intron, changing
the canonical AG to AA. Nucleotide 850 was involved; Curuk et al. (1995)
commented that a G-to-C change in the same nucleotide had been found in
a Yugoslavian family, whereas a frameshift due to deletion of nucleotide
850 was found in an Italian family. All 3 nucleotide changes lead to
beta-zero thalassemia and are rare in the populations in which they were
discovered.

.0455
HEMOGLOBIN HAKKARI
HBB, LEU31ARG

Gurgey et al. (1995) observed a highly unstable hemoglobin variant in a
5-year-old Turkish girl with severe hemolytic anemia without Heinz body
formation. A modest increase in liver and spleen size was present and
level of Hb F was 33%. The variant could not be observed in red cells
and was only detected through sequencing of the amplified beta-globin
gene and also by hybridization with specific oligonucleotide probes. The
variant was presumably a de novo mutation, since the parents were
normal. Smears from bone marrow aspirates showed numerous inclusion
bodies in erythroblasts and, as a result, erythroid hyperplasia. It was
suggested that this hemoglobin variant was unstable and readily lost its
heme group because one of the heme-binding sites had been lost and that,
as a result, it precipitates in erythroblasts, thus interfering with the
maturation process and causing severe anemia.

.0457
HEMOGLOBIN PUTTELANGE
HBB, ALA140VAL

In 2 sibs with polycythemia in a French family, Wajcman et al. (1995)
found a de novo ala140-to-val mutation. The hemoglobin displayed
increased oxygen affinity, thus explaining the polycythemia. Both
parents were phenotypically normal and study of polymorphic markers from
several chromosomes were consistent with paternity. Since 2 brothers
were affected, it was considered likely that the mutation had occurred
in the germline of the father.

.0458
HEMOGLOBIN ARTA
HBB, PHE45CYS

In a 22-year-old Caucasian female, known to be anemic from early
childhood and showing scleral subicterus and slightly enlarged spleen on
physical examination, Vassilopoulos et al. (1995) described a new
unstable hemoglobin variant with reduced oxygen affinity. A phe45-to-cys
amino acid substitution was found in beta-globin. The other chromosome
11 carried the gln39-to-ter (141900.0312) mutation that causes
beta-zero-thalassemia. The new variant was named for the Greek city
where the patient was born.

.0459
HEMOGLOBIN AURORA
HBB, ASN139TYR

In a 73-year-old female of Dutch descent, Lafferty et al. (1995) found
that a high oxygen affinity hemoglobin variant resulted from an
AAT-to-TAT transversion of codon 139, resulting in an asn139-to-tyr
amino acid substitution. See 141900.0092 for the asn139-to-asp mutation
and 141900.0108 for the asn139-to-lys mutation involving the same codon.

.0460
HEMOGLOBIN NAKANO
HBB, LYS8MET

During the assay of glycated hemoglobin by HPLC, Harano et al. (1995)
identified a new hemoglobin named Hb Nakano for the district of Tokyo
where healthy, 46-year-old Japanese woman lived and showed that it was
due to a change of codon 8 from lysine to methionine. See 141900.0135
for the lys8-to-gln mutation, 141900.0191 for the lys8-to-glu mutation,
and 141900.0237 for the lys8-to-thr mutation.

.0461
HEMOGLOBIN HINWIL
HBB, THR38ASN

Frischknecht et al. (1996) found a new hemoglobin variant in the course
of investigation of mild erythrocytosis. Mutation mapping of the
beta-globin gene by PCR and denaturing gradient gel electrophoresis
(DGGE) followed by sequence analysis revealed a C-to-A transversion at
codon 38, predicting a thr38-to-asn substitution. In contrast to the
other known mutation at codon 38, thr38-to-pro (known as Hb Hazebrouck;
141900.0101), Hb Hinwil was found to be stable and showed elevated
oxygen affinity.

.0462
HEMOGLOBIN DEBROUSSE
HBB, LEU96PRO

Lacan et al. (1996) described an unstable variant hemoglobin with high
oxygen affinity responsible, in the steady state, for an apparently
well-compensated chronic hemolytic anemia. The defect was shown to be a
leu96-to-pro substitution in the HBB gene. The hemoglobin was named for
the hospital in Lyon, France where the patient was observed. This
electrophoretically neutral hemoglobin was found as a de novo case in a
6-year-old girl suffering from severe anemia with hemolysis and
transient aplastic crisis following infection by parvovirus B19.

.0463
BETA-THALASSEMIA
HBB, 2-BP DEL, CC, CODONS 38-39

In 3 members of an indigenous Belgian family with beta-thalassemia
(613985), Heusterspreute et al. (1996) found a deletion of 2
nucleotides, CC, from codons 38 and 39. The mutation eliminates an AvaII
restriction site and so can be routinely investigated by AvaII digestion
of amplified DNA.

.0464
HEMOGLOBIN TSURUMAI
HBB, LYS82GLN

In a 46-year-old Japanese male with plethora and erythrocytosis, Ohba et
al. (1996) found a lys82gln amino acid substitution in the beta-globin
chain. A son also had erythremia due to this hemoglobin variant.

.0465
HEMOGLOBIN J (EUROPA)
HBB, ALA62ASP

In a 27-year-old man of Italian origin living in Belgium investigated
because of mild polycythemia with microcytosis, Kiger et al. (1996)
found that the hemoglobin had a negatively charged residue near the
distal histidine and an ala62-to-asp substitution. The variant was
called Hb J-Europa, presumably because it was found in the proband
during a systematic physical examination performed before employment at
the headquarters of the European Economic Community (EEC) in Luxembourg.

.0466
HB AUBENAS
HBB, GLU26GLY

Lacan et al. (1996) found this mildly unstable variant in a French
family without hematologic or clinical features. Although the
substitution involves the same residue as in Hb E (141900.0071), the new
sequence in this case did not create an additional out-of-frame splice
site. The mutated chain was, therefore, normally synthesized.

.0467
HB CAMPERDOWN
HBB, ARG104SER

Miranda et al. (1996) described Hb Camperdown in a 24-year-old Brazilian
woman of Italian origin. Although carriers do not show significant
clinical alterations, Hb Camperdown is considered an unstable Hb.

.0468
BETA-THALASSEMIA, DOMINANT
HBB, 3-BP INS, CGG, CODON 30

Negri Arjona et al. (1996) described a Spanish family with a dominant
type of beta-thalassemia (613985). Carriers were characterized by mild
anemia, hyperchromia, microcytosis, elevated Hb A2 and Hb F levels,
reticulocytosis, and splenomegaly. They found that the molecular basis
was the introduction of a CGG triplet between codons 30 and 31 of the
HBB gene; this was determined by sequencing of amplified DNA and
confirmed by dot-blot analysis. The abnormal mRNA was stable and present
in quantities similar to that of normal mRNA. The abnormal mRNA
translated into a beta-chain that was 147 amino acid residues long and
carried an extra arginine residue between residues 30 and 31. The
abnormal beta chain may be unstable and does not bind to the
alpha-chain. It probably is continuously digested by proteolytic enzymes
in red cell precursors in the bone marrow. The abnormal chain probably
binds haem that is excreted after proteolysis causing a darkening of
urine, which was a clinical characteristic of the disorder. The
insertion occurred at the 3-prime end of IVS1 and the 5-prime end of
exon 2. The insertion may have an addition of CGG between codons 30 and
31 or an insertion of GGC between IVS1 129/130.

.0469
HEMOGLOBIN COSTA RICA
HBB, HIS77ARG

Rodriguez Romero et al. (1996) discovered an abnormal beta-chain
hemoglobin Hb Costa Rica, or beta-his77arg, in a healthy young Costa
Rican female. This stable hemoglobin, termed Hb Costa Rica, was present
in only 6 to 8% of hemoglobin and was not observed in any relative (the
father was not available for study). The expected CAC-to-CGC mutation
could not be detected in genomic DNA. Smetanina et al. (1996) presented
convincing evidence that the CAG-to-CGC mutation at codon 77 of the HBB
gene had occurred as a somatic mutation during embryonic development and
resulted in mosaicism with only 6 to 8% of the abnormal Hb Costa Rica in
circulating red cells. Bradley et al. (1980) had described an instance
of gonadal mosaicism accounting for an unusual pedigree pattern in a
family with Hb Koln (141900.0151). Smetanina et al. (1996) incorrectly
stated that theirs was the first example of mosaicism in a hematopoietic
system.

.0470
BETA-THALASSEMIA, ASHKENAZI JEWISH TYPE
HBB, 1-BP INS, CODON 20/21, FS

Beta-thalassemia (613985) alleles are uncommon among Ashkenazi Jews as
compared with Sephardic Jews and other populations. Oppenheim et al.
(1993) described a rare allele, a single-base insertion resulting in a
frameshift at codon 20/21, in an Ashkenazi Jewish proband with
beta-thalassemia (613985) living in Israel. Martino et al. (1997)
independently discovered this allele (called fs20/21 by them) in a
Montreal Ashkenazi pedigree and investigated the possibility of
genealogic connections between the 2 families. They showed by analysis
of the mutation and the associated marker haplotype that the Israeli and
Montreal probands appeared to be identical by descent and certainly had
identity by state at the HBB locus. Genealogic reconstruction suggested
that the 2 families had a shared origin in time and space.

.0471
HB NIIGATA
HBB, VAL1LEU

Ohba et al. (1997) reported the fifth variant with retention of the
initiator methionine and partial acetylation. The proband, a 37-year-old
Japanese male, was subjected to detailed studies because of an
unexpectedly high HbA1c value on cation exchange high performance liquid
chromatography. The findings of their subsequent studies, as well as
previous reports, suggested that retention of the initiator methionine
and acetylation have no physiologic or pathologic significance, at least
on human hemoglobin. The authors found that the variant hemoglobins were
not unstable in in vitro tests. Ohba et al. (1997) stated that they must
be almost as stable as normal HbA in vivo because they comprise over 40%
of total Hb in the peripheral blood. The 4 previously reported Hb
variants with retention of initiator methionine were Hb Thionville
(141800.0168), Hb Marseille (141900.0171), Hb Doha (141900.0069), and Hb
South Florida (141900.0266).

.0472
BETA-ZERO-THALASSEMIA
HBB, 5-BP DEL AND 1-BP INS

Waye et al. (1997) described a beta-thalassemia (613985) trait in a
Caucasian woman of British descent living in Ontario, Canada. The
48-year-old woman presented with typical high Hb A2 beta-thalassemia
trait. All known family members were of British ancestry. Her father had
normal hematologic indices and her mother was deceased. There was no
family history of anemia. Direct nucleotide sequencing demonstrated a
complex frameshift mutation due to deletion of 5 nucleotides (AGTGA) and
insertion of 1 nucleotide (T) at codons 72/73 of the HBB gene. This
introduced a premature stop codon (TGA) at codon 88, resulting in
beta-zero-thalassemia.

.0473
HB GAMBARA
HBB, LYS82GLU

In a Lombardy family (from Gambara, near Brescia in Northern Italy),
Ivaldi et al. (1997) described a 45-year-old man and his 2 daughters who
carried an abnormal hemoglobin resulting in modest erythrocytosis and
mild, compensated hemolysis with slight splenomegaly. The abnormal
hemoglobin represented about 52% of the total hemoglobin, and was shown
to be stable by the isopropanol test. Sequencing demonstrated a change
in the HBB gene of codon 82 from AAG (lys) to GAG (glu) in heterozygous
state.

.0474
BETA-ZERO-THALASSEMIA
HBB, IVS1AS, A-G, -2

Waye et al. (1998) studied the hemoglobin of a 37-year-old woman who
presented during pregnancy with the beta-thalassemia (613985) trait. The
father and mother were Sephardic Jews whose families had lived for many
generations in Tangiers and Gibraltar, respectively. The HBB gene was
found to have a single basepair substitution at codon 30: AGG (arg) to
GGG (gly). The mutation changed the sequence immediately upstream of the
5-prime splice junction of the first intron: A-to-G at position -2 of
IVS1. The authors stated that although mutations had been found at
positions -1 and -3 of IVS1, no mutation had been described at the -2
position. The authors thought it unlikely that an arg30-to-gly
substitution was responsible for the abnormality and favored the
possibility that the mutation impaired the normal splicing of the
beta-globin pre-mRNA.

Li et al. (1998) identified the same mutation in a Chinese man whose
wife carried the 4-bp deletion at codons 41/42 (141900.0326) that is a
common beta-thal mutation in Japanese. Their son had died of severe
anemia at age 4 and the authors speculated that he had
beta-0-thalassemia due to compound heterozygosity for these mutations.

.0475
BETA-ZERO-THALASSEMIA
HBB, 1-BP INS, T, CODON 26

Hattori et al. (1998) identified a new beta-thalassemia (613985) allele
in a 31-year-old Japanese man who was found to have microcytosis and
erythrocytosis during a health check-up. His red blood cell count was
6.53 x 10(12) per liter. The HBB gene in 1 allele was found to have an
insertion of T at codon 26: GAG-to-GTAG. The frameshift mutation was
expected to result in beta-zero-thalassemia because the translation of
the abnormal mRNA produced a peptide with an abnormal amino acid
sequence from codon 26 to 42 where it terminates. Such a truncated
peptide of 42 residues would be immediately eliminated by proteolysis.
Codon 26 is involved in the consensus sequence for cryptic splicing at
codon 25. The insertion of T at codon 26 breaks the consensus sequence
and is unlikely to affect the alternative splicing. Results of SSCP
analysis indicated that the patient was heterozygous for the frameshift.

.0476
HEMOGLOBIN SILVER SPRINGS
HBB, GLN131HIS

Hoyer et al. (1998) described a new hemoglobin variant called Hb Silver
Springs which resulted from a CAG (gln)-to-CAC (his) change at codon 131
of the beta chain. It was detected only by cationic exchange high
performance liquid chromatography. This was the fifth reported
substitution at codon 131. The variant did not appear to have any
clinical or hematologic manifestations. It was found in 6 African
Americans from 4 presumably unrelated families.

.0477
HEMOGLOBIN BURTON-UPON-TRENT
HEMOGLOBIN OLD DOMINION
HBB, HIS143TYR

In investigating the nature of the unique hemoglobin variant that caused
a spurious increase in glycated hemoglobin, Hb A(1c), Elder et al.
(1998) found a CAC-to-TAC mutation in the HBB gene that resulted in a
his143-to-tyr substitution in the beta-globin peptide. This amino acid
substitution affected an important 2,3-diphosphoglycerate binding site
and slightly increased the oxygen affinity of the hemoglobin variant.
Despite the slight increase in oxygen affinity, the mutation was without
hematologic effect, and its only clinical significance was that it
coeluted with Hb A(1c) on ion-exchange chromatography and compromised
the use of this analyte to monitor the treatment of diabetes mellitus.
The variant was encountered in 4 unrelated persons of Irish or
Scottish-Irish ancestry.

Gilbert et al. (2000) reported 2 unrelated cases of Hb Old
Dominion/Burton-upon-Trent.

Plaseska-Karanfilska et al. (2000) found the same mutant hemoglobin in a
72-year-old Korean woman with type II diabetes (125853).

.0478
HEMOGLOBIN RIO CLARO
HBB, VAL34MET

By globin chain electrophoresis, Grignoli et al. (1999) detected a novel
silent hemoglobin variant in a 4-year-old Caucasian Brazilian boy of
Italian descent, and in his mother. Sequencing of the HBB gene revealed
a G-to-A transition at the first position of codon 34, resulting in a
val-to-met substitution. In the boy, this variant was found to be
associated with Hb Hasharon (141850.0012) and alpha-thalassemia-2
(rightward deletion).

.0479
HEMOGLOBIN NIJKERK
HBB, 4-BP DEL/1-BP INS, CODONS 138/139, GCTA/T

Van den Berg et al. (1999) identified a novel Hb B variant, termed Hb
Nijkerk, in a Caucasian Dutch girl who was slightly icteric at birth and
developed hemolytic anemia and hepatosplenomegaly at about 5 months of
age. Red cell transfusions were necessary every 3 to 4 weeks.
Erythromorphology was markedly abnormal, with large numbers of red cells
with inclusion bodies. Splenectomy was performed at the age of 18
months, after which the need for transfusions decreased and they were
finally discontinued. Although still anemic, the child's growth was
otherwise normal. Repeated hemoglobin electrophoresis on cellulose
acetate revealed no abnormalities. At the age of 17 years, a minor
abnormal band, migrating slightly faster than Hb A2, was detected on
starch gel electrophoresis. Sequencing of the HBB gene revealed
heterozygosity for a 4-bp deletion (GCTA) in combination with a 1-bp
insertion (T) at codons 138/139. This event eliminated 2 amino acids
(ala and asn) and introduced a new residue (tyr) into the protein. The
parents did not carry the mutation and paternity analysis showed no
discrepancies, indicating that Hb Nijkerk should be considered as a de
novo event.

.0480
HEMOGLOBIN CHILE
HBB, LEU28MET

Hojas-Bernal et al. (1999) identified a novel Hb B gene variant, termed
Hb Chile, in a 57-year-old Native American living in Chile who was known
to be chronically cyanotic. He was hospitalized for elective surgery of
left pyeloureteral stenosis. Prior to surgery, he was given
sulfonamides. Surgery was terminated when the dark color of his blood
was noted. Arterial oxygen saturation was 80%. His blood contained 18%
methemoglobin. Repeated intravenous methylene blue was given for the
methemoglobinemia but to no avail. Sulfhemoglobin was not increased.
Subsequently, an acute episode of hemolytic anemia occurred. Red cell
glucose-6-phosphate dehydrogenase and methemoglobin reductase were
normal. The patient's father and 1 of his 2 children also showed
cyanosis. Tryptic digestion of the beta-globin chain and subsequent
chromatography revealed an abnormal beta-T-3 peptide; sequencing
revealed a leu-to-met substitution at position 28, predicted to be
caused by a CTG-to-ATG transversion in the HBB gene. Hojas-Bernal et al.
(1999) concluded that Hb Chile is an unstable hemoglobin that forms
methemoglobin in vivo spontaneously at an accelerated rate and
predisposes to drug-induced hemolytic anemia.

.0481
HEMOGLOBIN TENDE
HBB, PRO124LEU

By chromatographic measurement of glycated Hb in a 90-year-old woman of
French origin, Wajcman et al. (1998) identified a novel hemoglobin
variant, termed Hb Tende, that showed a moderate increase in oxygen
affinity. Sequencing of the HBB gene revealed a CCA-to-CTA transition,
resulting in a pro124-to-leu substitution. Three hemoglobin variants at
amino acid 124 had been previously described: Hb Tunis (pro124 to ser;
141900.0288) is asymptomatic; Hb Khartoum (pro124 to arg; 141900.0148)
is mildly unstable; and Hb Ty Gard (pro124 to gln; 141900.0289) is
responsible for increased oxygen affinity leading to erythrocytosis.
Wajcman et al. (1998) suggested that the absence of erythrocytosis in
the Hb Tende carrier whom they studied was likely due to the relatively
low proportion of abnormal Hb (34%), possibly explained by the mild
instability revealed by the isopropanol test, and to the normal
cooperativity of the variant.

.0482
HEMOGLOBIN LA ROCHE-SUR-YON
HBB, LEU81HIS

Wajcman et al. (1992) identified Hb La Roche-sur-Yon, an unstable
hemoglobin variant resulting from a leu81-to-his substitution in the HBB
gene. The variant displayed a moderately increased oxygen affinity. in
addition to the substitution at beta-81, about half the abnormal
hemoglobin carried a deamidation of the neighboring asparagine residue
at beta-80. The authors concluded that the deamidation depends not only
on the flexibility of the polypeptide region but also on the presence of
a neighboring histidine residue to catalyze the reaction. See also Hb
Redondo (141900.0404).

.0483
HEMOGLOBIN IRAQ-HALABJA
HBB, ALA10VAL

In a family originating from Iraq, Deutsch et al. (1999) identified a
novel beta-chain silent variant, a change of codon 10 from GCC to GTC
(ala10 to val), in association with thalassemia. The variant, which they
designated Hb Iraq-Halabja, gave a normal oxygenation curve, a normal
heterotopic action of 2,3-DPG, and normal heat stability and isopropanol
precipitation tests. The variant showed a clear difference in migration
properties compared to normal beta chain only when run on PAGE urea
Triton. The codon involved in Hb Iraq-Halabja is the same as that mutant
in Hb Ankara (141900.0009), in which the substitution is ala10 to asp.

.0484
HEMOGLOBIN LUCKNOW
HBB, LYS8ARG

Agarwal et al. (1999) found an A-to-G transition in exon 1 of the HBB
gene at codon 8 which resulted in a lys8-to-arg amino acid substitution.
This change was associated with a splice mutation and was speculated to
produce a thalassemia intermedia phenotype in the subject.

.0485
HEMOGLOBIN SAGAMI
HBB, ASN139THR

Miyazaki et al. (1999) described compound heterozygosity for a
beta(+)-thalassemia mutation and a new beta variant with low oxygen
affinity, Hb Sagami (asn139 to thr).

.0486
HEMOGLOBIN HARROW
HBB, PHE118CYS

Henthorn et al. (1999) reported a new beta-globin variant, phe118 to
cys, found in a newborn male of Indian Gujerati origin, living in the
Harrow area of London, England. This variant was observed during a
systematic program of neonatal screening. The mother also carried the
abnormal hemoglobin.

.0487
HEMOGLOBIN BRIE COMTE ROBERT
HBB, PRO36ALA

Wajcman et al. (1999) described a beta-globin variant in a 36-year-old
French Caucasian male who presented with polycythemia. The variant was
named Hb Brie Comte Robert for the place where the carrier resided. It
was shown to have high oxygen affinity.

.0488
HEMOGLOBIN BARBIZON
HBB, LYS144MET

In several members of a French family, Kister et al. (1999) identified a
lys144-to-met mutation in the HBB gene. The mutation is a clinically
silent variant in which the structural modification disturbs the
oxygen-linked chloride binding.

.0489
HEMOGLOBIN BOLOGNA-ST. ORSOLA
HBB, HIS146TYR

In 3 members of a family from Bologna, Italy, Ivaldi et al. (1999)
demonstrated that erythrocytosis was the result of a variant beta-globin
chain, a CAC-to-TAC mutation in codon 146 leading to a his146-to-tyr
amino acid substitution. Ivaldi et al. (1999) pointed out that this was
the sixth substitution that had been identified in the C-terminal
residue of the beta-globin chain, the others being his146-to-asp
(141900.0110), his146-to-pro (141900.0305), his146-to-leu (141900.0056),
his146-to-arg (141900.0051), and his146-to-gln (141900.0409).

Gilbert et al. (2000) described a second case of Hb Bologna-St. Orsola
in a family of Anglo-Celtic origin.

.0490
HEMOGLOBIN VILA REAL
HBB, PRO36HIS

In a 15-year-old Portuguese girl with erythrocytosis, Bento et al.
(2000) found a new high oxygen affinity variant called Hb Vila Real and
characterized by a pro36-to-his (P36H) missense mutation of the HBB
gene. The patient's mother had undergone regular phlebotomies over the
previous 20 years for polycythemia, with an obstetric history of 2
miscarriages, a stillborn baby, and 2 normal children by elective
Cesarean section. A transversion converted codon 36 from CCT to CAT. The
variant was named after the city in Portugal where the carrier was born.

Salzano et al. (2002) reported the same rare high oxygen affinity
hemoglobin variant in a 22-year-old male patient from Naples, Italy,
affected by erythrocytosis. The DNA mutation was identified as a change
in codon 36 of the HBB gene from CCT to CAT. The father carried the same
hemoglobin variant in heterozygous state.

.0491
HEMOGLOBIN SAALE
HBB, THR84ALA

In a 3-year-old anemic German girl, Bisse et al. (2000) detected an
abnormal hemoglobin by cation-exchange high performance liquid
chromatography. Further studies characterized the variant as a
thr84-to-ala replacement in the HBB gene, which the authors named Hb
Saale for the river crossing the city in which the proband lived. Hb
Saale could be not be separated by electrophoresis or isoelectric
focusing. It was found to be slightly unstable, exhibiting a moderate
tendency to autooxidize. Functional properties and the heterotropic
interactions were similar to those of hemoglobin A.

.0492
HEMOGLOBIN BUSHEY
HBB, PHE122LEU

Wajcman et al. (2000) found a hemoglobin variant, designated Hb Bushey,
in a Chinese baby and his father. The variant was found to be caused by
a point mutation leading to a phe122-to-leu substitution in the HBB
gene. The same amino acid substitution was found in Hb Casablanca
(141900.0493), in combination with another abnormality in the HBB gene,
i.e., a lys65-to-met amino acid substitution (Hb J (Antakya);
141900.0121).

.0493
HEMOGLOBIN CASABLANCA
HBB, LYS65MET AND PHE122LEU

Wajcman et al. (2000) found a hemoglobin variant in a family in Morocco
and designated it Hb Casablanca. It was found to be another example of a
hemoglobin variant with 2 abnormalities in the same chain: the first was
identical to that of Hb Bushey (phe122 to leu; 141900.0492) and the
second to that of Hb J (Antakya) (lys65 to met; 141900.0121). The
stability and oxygen-binding properties of Hb Bushey and Hb Casablanca
were identical to those of Hb A.

.0494
HEMOGLOBIN TSUKUMI
HBB, HIS117TYR

Oribe et al. (2000) found a new hemoglobin variant in a Japanese male: a
change at codon 117 of the HBB gene from CAC (his) to TAC (tyr). The
authors designated this variant Hb Tsukumi after the patient's place of
residence. Two other hemoglobin variants have a change in his117: a
change to arg in the case of Hb P (Galveston) (141900.0213), and a
change to pro in the case of Hb Saitama (141900.0250).

North et al. (2001) found Hb Tsukumi in a Moroccan woman.

.0495
HEMOGLOBIN ERNZ
HBB, THR123ASN

Analysis of globin chains by reversed phase high performance liquid
chromatography, used as an additional tool for characterizing hemoglobin
variants, led to the discovery of a new class of variants that display
only differences in hydrophobicity. Groff et al. (2000) described 2 such
variants: Hb Ernz and Hb Renert (141900.0496). Hb Ernz, a thr123-to-asn
substitution, was found in a man of Italian origin who was polycythemic
and in 2 of his 3 daughters who were hematologically normal. See
141900.0294 for a thr123-to-ile substitution.

.0496
HEMOGLOBIN RENERT
HBB, VAL133ALA

Groff et al. (2000) identified Hb Renert, a val133-to-ala substitution
in the HBB gene, in a man from Cape Verde who also carried Hb S
(141900.0243) and presented with chronic hemolysis.

Wilson et al. (2001) described a second case of Hb Renert. They
commented that this was only the second hemoglobin variant involving
beta-133, the other being Hb Extremadura (V1133L; 141900.0074).

.0497
HEMOGLOBIN WATFORD
HBB, VAL1GLY

Four hemoglobin variants had previously been described that involve the
first codon of the HBB gene: Hb Doha (141900.0069), Hb South Florida
(141900.0266), Hb Niigata (141900.0471), and Hb Raleigh (141900.0233).
Although none of these variants cause any significant clinical problems,
mutations of the first codon are of interest because of their potential
interference with cotranslational modification at this site during
beta-globin synthesis. In eukaryotes, the translation of all peptide
mRNAs starts at an AUG codon, producing methionine at the beginning of
the nascent peptide chain. In most proteins, including alpha-, beta-,
and gamma-globin, this methionine is cotranslationally cleaved when the
chain is 20 to 30 amino acids long. This results in the first amino acid
being valine in alpha-, beta-, and delta-globin, and glycine in
gamma-globin. When the peptide chain is 40 to 50 amino acids long,
further modification occurs with acetylation at the NH2-terminal
residue. The extent of the acetylation depends on the identity of the
N-terminal amino acid; valine is strongly inhibitory to this process,
leading to little acetylation of alpha- and beta-globin. However, the
N-terminal glycine of gamma-globin is less inhibitory, resulting in
about 15% acetylation. Fisher et al. (2000) identified a new Hb variant,
Hb Watford, in which a GTG-to-GGG substitution caused a change of the
first amino acid of the beta-globin chain from methionine to glycine,
mimicking the gamma-globin chain. The proband was a 48-year-old female
of Jewish extraction who was evaluated for chronic mild anemia. Another
mutation was found in cis with the val1-to-gly mutation: Cap+36G-A.

.0498
HEMOGLOBIN YAOUNDE
HBB, VAL134ALA

Yapo et al. (2001) described a val134-to-ala missense mutation of the
HBB gene in a 45-year-old man originating from Cameroon, a migrant
worker in France. He was a compound heterozygote for this mutation,
designated Hb Yaounde, and for Hb Kenitra (141900.0147). Hb Kenitra had
previously been described only in persons of Moroccan origin. Hb Yaounde
appeared to be neutral; Hb Kenitra is associated with expression at a
level slightly higher than that of Hb A.

Faustino et al. (2004) described Hb Yaounde in a 3-generation Portuguese
family. The proband had compound heterozygosity for this hemoglobin
variant and for hemoglobin C (glu6 to lys; 141900.0038). Hb Yaounde was
associated with the Mediterranean haplotype II, supporting the
hypothesis of a genetic origin independent of the African origin.

.0499
HEMOGLOBIN SITIA
HBB, ALA128VAL

Papassotiriou et al. (2001) identified hemoglobin Sitia, an
ala128-to-val missense mutation in the HBB gene, in a Greek female with
slightly reduced red blood cell indices.

.0500
HEMOGLOBIN MONT SAINT-AIGNAN
HBB, ALA128PRO

In a 33-year-old French Caucasian woman displaying a well-tolerated
chronic anemia, Wajcman et al. (2001) found Hb Mont Saint-Aignan, a
mildly unstable variant associated with hemolytic anemia, marked
microcytosis, and increased alpha/beta biosynthetic ratio. The molecular
defect was an ala128-to-pro missense mutation of the HBB gene.

.0501
HEMOGLOBIN 'T LANGE LAND
HBB, GLY136ARG

In a Dutch patient of Chinese origin, Harteveld et al. (2001) identified
a new hemoglobin variant, Hb 't Lange Land, caused by a GGT-to-CGT
transversion at codon 136 in exon 3 of the HBB gene, predicted to result
in a gly136-to-arg (G136R) substitution. The authors stated that 3
mutations inducing a single amino acid substitution at codon 136 were
known: Hb Hope (gly136 to asp; 141900.0112), and 2 others based on
personal communication from H. Wajcman, Hb Petit Bourg (gly136 to ala)
and Hb Perpignan (gly136 to ser).

.0502
HEMOGLOBIN D (AGRI)
HBB, SER9TYR AND GLU121GLN

In an asymptomatic Indian male belonging to the Agri caste group and
originating from Mumbai in Maharashtra State, India, Colah et al. (2001)
found a new hemoglobin variant, Hb D (Agri), with 2 amino acid
substitutions in the same beta chain: glu121 to gln (141900.0065) and
ser9 to tyr.

.0503
HEMOGLOBIN ANTALYA
HBB, 9-BP DEL/INS

Keser et al. (2001) identified a 9-bp (TCTGACTCT) deletion/insertion at
codons 3-5 of the HBB gene in a 26-year-old woman with beta-thalassemia
trait. The change was found to be the result of a deletion of cytosine
(-C) at codon 5 (1 of the nucleotides in the thirteenth or fourteenth
position of exon 1), and an insertion of thymine (+T) in front of codon
3 at the tenth nucleotide in exon 1 of the HBB gene. As a result of
these mutations, the amino acids at codons 3-5 were changed from
leu-thr-pro to ser-asp-ser. This partial frameshift mutation led to a
very unstable beta-globin chain.

.0504
HEMOGLOBIN LIMASSOL
HBB, LYS8ASN

Kyrri et al. (2001) found a nonpathologic Hb variant in a Greek Cypriot
male originating from Limassol, a town on the south coast of Cyprus. A
G-to-C substitution in codon 8 (AAG to AAC) led to a lys8-to-asn (K8N)
amino acid substitution. The 4 previously described amino acid
substitutions at residue 8 of the beta-globin chain (lys8 to thr,
141900.0237; lys8 to gln, 141900.0135; lys8 to glu, 141900.0191; and
lys8 to met, 141900.0460), and the 2 hemoglobin variants with amino acid
substitutions at the equivalent residue of the alpha-globin chain (lys7
to asn, 141800.0187 and lys7 to glu, 141800.0192) are nonpathologic as
well.

.0505
THALASSEMIA INTERMEDIA
HBB, DEL, SOMATIC

Badens et al. (2002) described a 'new' mechanism leading to thalassemia
intermedia (613985), a moderate form of thalassemia: a somatic deletion
of the HBB gene in the hemopoietic lineage of a heterozygous
beta-thalassemic patient. The deletion occurred on the chromosome 11
inherited from the mother, who had no abnormality of the HBB gene. The
father had a beta-thalassemic trait due to the Mediterranean HBB
nonsense mutation (141900.0312). The deletion gave rise to a mosaic of
cells with either 1 or no functional beta-globin gene and it extended to
a region of frequent loss of heterozygosity called LOH11A, which is
located close to the HBB locus. Thus, loss of heterozygosity can be a
cause of nonmalignant genetic disease.

.0506
HEMOGLOBIN CANTERBURY
HBB, CYS112PHE

Brennan et al. (2002) found hemoglobin Canterbury by chance when a
supposedly normal lysate was used as a control for an isopropanol
stability test. The sample came from a 55-year-old man with Cowden
disease (601728). The isopropanol stability test showed a precipitate,
suggesting a slightly unstable hemoglobin.

.0507
HEMOGLOBIN O (TIBESTI)
HBB, GLU121LYS, VAL11ILE

Prehu et al. (2002) described a heterozygous hemoglobin variant that
combined the change of Hb O-Arab (141900.0202) and Hb Hamilton
(141900.0099) on the same HBB allele. The other allele carried the Hb S
mutation (141900.0243). The patient was a child of Chad-Sudanese
descent, suffering from a sickle cell syndrome. Compared to the classic
description of the Hb S/Hb O-Arab association, the additional Hb
Hamilton mutation did not seem to modify the clinical presentation.

.0508
HEMOGLOBIN MOLFETTA
HBB, VAL126LEU

Qualtieri et al. (2002) identified a new neutral hemoglobin variant in a
pregnant Italian woman that resulted from a GTG-to-CTG replacement at
codon 126 of the HBB gene, corresponding to a val-to-leu amino acid
change. Thermal and isopropanol stability tests were normal and there
were no abnormal clinical features.

.0509
BETA-THALASSEMIA, DOMINANT
HBB, 1-BP DEL

Waye et al. (2002) described a case of dominant beta-thalassemia
(613985) in a 38-year-old Canadian male of northern European extraction.
He was anemic at birth and required periodic blood transfusions until
about 2 years of age. Subsequently, he was under close medical
supervision for his anemia and thrombocytosis, but did not require
further transfusions. He had been asymptomatic throughout childhood. At
age 20 years, he was found to have splenomegaly, and splenectomy was
performed at age 23 because of mild symptoms and to prevent splenic
rupture during karate competitions. After surgery he received Pneumovax,
a prophylaxis against pneumococcal infections. He remained on folic acid
supplementation, which had been started in childhood. The family history
was negative for hematologic disorders. He was shown to have the normal
complement of 4 alpha-globin genes. He was heterozygous for a
single-nucleotide deletion in the HBB gene converting codon 113 from GTG
to TG. This frameshift mutation was predicted to give rise to an
extended beta chain of 156 amino acid residues. It was considered to be
a de novo mutation. The mutation in this case most closely resembled
that of Hb Geneva (141900.0335), an unstable beta-chain variant due to a
complex rearrangement at codon 114. Both mutations give rise to extended
beta chain variants of 156 amino acids differing only at residues 113
and 114 (cys-val for the codon 113 mutation and val-gly for the codon
114 mutation). In both instances, it was not possible to detect even a
trace of the predicted Hb variant in carriers of the mutation.

Waye et al. (2002) stated that more than 30 dominant beta-thalassemia
alleles had been reported.

.0510
HEMOGLOBIN KODAIRA II
HBB, HIS146GLN

So et al. (2002) described a 35-year-old woman in whom a beta-chain
variant was found on assay for Hb A(1c) performed because of impaired
glucose tolerance during pregnancy. The raised hemoglobin level was
suggestive of a hemoglobin variant with high oxygen affinity. The
patient was heterozygous for a CAC-to-CAG transversion at codon 146,
corresponding to a substitution of histidine by glutamine in the
beta-globin chain. The same amino acid substitution at codon 146 occurs
in the high oxygen affinity variant Hb Kodaira (141900.0409); however,
Hb Kodaira resulted from a point mutation of CAC-to-CAA at codon 146.
Not unexpectedly, the phenotypic manifestation of the 2 mutations was
identical. This second form of his146 to gln (H146Q) was referred to as
hemoglobin Kodaira II.

Ngiwsara et al. (2003) described a case of Hb Kodaira II in Thailand.

.0511
HEMOGLOBIN ILMENAU
HBB, PHE41CYS

Prehu et al. (2002) described a novel unstable hemoglobin variant with
low oxygen affinity and called it Hb Ilmenau for the city where the
patient lived. The variant hemoglobin had a phe41-to-cys (F41C)
substitution due to a TTC-to-TGC transversion in codon 41. The patient
was a 29-year-old man who had suffered from anemia since childhood. When
he was 4 years old, a nonspherocytic anemia was diagnosed with
hepatosplenomegaly and cyanosis for which no cardiac origin could be
found. He was splenectomized at the age of 8 years, without any
significant clinical or biologic improvement.

.0512
HEMOGLOBIN AUBAGNE
HBB, GLY64ALA

In a 32-year-old woman from Provence, southeast France, Lacan et al.
(2002) found a novel unstable beta-chain variant with a GGC-GCC
transversion resulting in a gly64-to-ala (G64A) substitution. The
presence of Heinz bodies and reduced percentage (23 to 35%) of the
abnormal hemoglobin fraction suggested a moderate instability in the
hemoglobin, which the authors designated Hb Aubagne.

.0513
HEMOGLOBIN COLIMA
HBB, SER49CYS

Cobian et al. (2002) found Hb Colima, a ser49-to-cys change (S49C) of
the beta-globin chain, in a 52-year-old Mestizo female who was born in
Colima, Mexico. This was the second mutation at beta-49, the first being
Hb Las Palmas (ser49 to phe), a slightly unstable variant (141900.0155).

.0514
HEMOGLOBIN POCOS DE CALDAS
HBB, LYS61GLN

During a screening for hemoglobinopathies in blood donors in Brazil,
Kimura et al. (2002) identified a beta-globin variant in a 30-year-old
Caucasian woman of mixed Native Indian and Italian origin. The base
substitution in codon 61 of the HBB gene from AAG to CAG caused a
lys-to-gln (K61Q) change. This was the fourth description of a missense
mutation at lys61 of the HBB gene: see Hb N-Seattle (K61E; 141900.0190),
found in a black American blood donor; Hb Hikari (K61N; 141900.0106),
found in a Japanese family; and Hb Bologna (K61M; 141900.0024), found in
a northern Italian family. The missense mutations found at this position
(external contacts of the Hb molecule) did not cause clinical
manifestations; all the carriers described had been asymptomatic.

.0515
HEMOGLOBIN TRENTO
HBB, 1-BP DEL, 144A

In a 31-year-old woman from Trento in northeastern Italy, Ivaldi et al.
(2003) found anomalous hemoglobin: an elongated C-terminal variant due
to deletion of an A in codon 144. The deletion led to the replacement of
lysine by serine at residue 144, the disappearance of the stop codon at
position 147, and the presence of 12 additional residues, identical to
those observed in hemoglobins Saverne (141900.0255), Tak (141900.0279),
and Cranston (141900.0057), which result from a similar mechanism. Hb
Trento, amounting to 29% of the total hemoglobin, was unstable and, like
the other variants of this group, had an increased oxygen affinity. It
led to a mild compensated hemolytic anemia with red cell inclusion
bodies.

.0516
HEMOGLOBIN SANTANDER
HBB, VAL34ASP

In a 22-year-old Spanish male presenting with jaundice and suffering
from hemolytic crises during infections, Villegas et al. (2003)
identified an unstable Hb variant in which the valine residue at
position 34 of the beta-globin chain was replaced by aspartic acid
(val34 to asp; V34D).

.0517
HEMOGLOBIN BUZEN
HBB, ALA138THR

During glycohemoglobin determination by HPLC in a 76-year-old Japanese
woman, Miyazaki et al. (2003) identified a homozygous change of codon
138 of the HBB gene from GCT (ala) to ACT (thr) (A138T). No information
on the clinical state of the patient was provided. In Hb Brockton
(141900.0032), ala138 is changed to pro. Heinz body hemolytic anemia has
been observed with that mutation.

.0518
HEMOGLOBIN SANTA CLARA
HBB, HIS97ASN

In a 6-month-old infant and in her mother of Mexican ancestry who lived
in San Jose, California, Hoyer et al. (2003) identified a hemoglobin
variant with abnormal oxygen affinity, designated Hb Santa Clara. A
change of codon 97 of the HBB gene from CAC to AAC resulted in a
his97-to-asn (H97N) change. Both the infant and her mother exhibited
mild erythrocytosis.

.0519
HEMOGLOBIN SPARTA
HBB, PHE103VAL

In a 29-year-old Caucasian woman who lived near Sparta, Michigan, Hoyer
et al. (2003) identified a hemoglobin variant with high oxygen affinity,
designated Hb Sparta. A smoker of 1 pack per day for 15 years, she was
found to have mild erythrocytosis. A change of codon 103 of the HBB gene
from TTC to GTC resulted in a phe103-to-val (F103V) change. Phe103 is
replaced by leu in Hb Heathrow (141900.0102), and by ile in Hb Saint
Nazaire (141900.0436); both variants are associated with erythrocytosis.

.0520
BETA-THALASSEMIA, DOMINANT INCLUSION BODY TYPE
HBB, INS/DEL, EX3

Weatherall et al. (1973) described an Irish family with an unusual form
of beta-thalassemia (613985) that was characterized by anemia,
splenomegaly, and gross abnormalities of the erythrocytes and their
precursors; the disorder was transmitted through several generations in
an autosomal dominant fashion. Initially the disorder was labeled
dyserythropoietic anemia, congenital, Irish or Weatherall type (603902).
Thein et al. (1990) restudied the Irish family and 3 similarly affected
kindreds, all of Anglo-Saxon origin, and pointed to similar cases
reported by others and to the fact that the designation inclusion body
beta-thalassemia had been proposed (Stamatoyannopoulos et al., 1974).
All affected members of the original Irish family had a moderate anemia
with splenomegaly, increased levels of Hb A2 and Hb F, and increased
alpha/beta chain synthesis ratios. Two family members had undergone
splenectomy. By the time of the report of Thein et al. (1990), 1 family
member had died, showing at autopsy extensive extramedullary hemopoiesis
and iron overload in parenchymal tissues in a pattern typical of
excessive iron absorption rather than transfusion. The family had a
complex rearrangement in the third exon of the HBB gene that involved 2
deletions, 1 of 4 bp in codons 128 and 129 and the other of 11 bp in
codons 132-135. The deletions were interrupted by an insertion of 5 bp,
CCACA, followed by the normal sequence of 8 nucleotides. The
modification resulted in a frameshift reading through to codon 153,
predicting the synthesis of a variant beta-globin 7 residues longer than
normal. Thein et al. (1990) suggested that the phenotypic difference
between this condition and the more common recessive forms of
beta-thalassemia lies mainly in the length and stability of the abnormal
translation products that are synthesized and, in particular, whether
they are capable of binding heme and producing aggregations that are
relatively resistant to proteolytic degradation.

.0521
HEMOGLOBIN S (CAMEROON)
HBB, GLU6VAL AND GLU90LYS

Bundgaard et al. (2004) described a hemoglobin variant with 2 amino acid
substitutions: Hb S, which is a glu6-to-val substitution (G6V;
141900.0243), and Hb Agenogi, which is a glu90-to-lys substitution
(G90K; 141900.0003). As the patient originated from Cameroon, the
variant was designated Hb S (Cameroon). The authors stated that 4 double
mutations on the same allele with the Hb S variant had previously been
described: Hb S (Antilles) (141900.0244), Hb S (Providence)
(141900.0246), Hb S (Oman) (141900.0245), and Hb S (Travis)
(141900.0247).

.0522
HEMOGLOBIN CARDARELLI
HBB, ALA86PRO

In several members of a family from Naples, Italy, Pagano et al. (2004)
identified a change of codon 86 of the HBB gene from GCC (ala) to CCC
(pro) (A86P). The variant, which is unstable and has high oxygen
affinity, was designated Hb Cardarelli. The A86P mutation had previously
been found in the doubly substituted, unstable, and hyperaffine variant
Hb Poissy (141900.0223), in which it occurs in combination with
gly56-to-arg of Hb Hamadan (G56R; 141900.0098).

.0523
HEMOGLOBIN JAMAICA PLAIN
HBB, GLU6VAL AND LEU68PHE

Geva et al. (2004) described a girl of Puerto Rican descent who
presented with symptomatic sickle cell disease exacerbated by mild
hypoxemia, despite a newborn screening diagnosis of sickle cell trait.
The child was found to be heterozygous for mutations in the HBB gene:
the sickle cell mutation glu6 to val (G6V; 141900.0243), and a neutral
leu68-to-phe (L68F; 141900.0524) mutation. Analysis of the patient's
hemoglobin demonstrated that the doubly mutant protein, which the
authors called hemoglobin Jamaica Plain (Hb JP) for Jamaica Plain,
Massachusetts, had severely reduced oxygen affinity, especially in the
presence of 2,3-diphosphoglycerate. Structural modeling suggested
destabilization of the oxy conformation as a molecular mechanism for
sickling in a heterozygote at an ambient partial pressure of oxygen. The
patient's sickle cell disease was exacerbated by intercurrent
respiratory infection, and she developed splenomegaly. The splenomegaly
and anemia were recurrent. At the age of 19 months, during her first
airplane trip, the child became acutely ill, with her spleen reaching
the pelvic brim, as reported by a physician on board. After landing, she
was hospitalized and found to have a hematocrit of 18%. Packed red cells
were transfused; the hematocrit then rose to 28% with resolution of
symptoms and a decrease in splenomegaly. Because of the apparent splenic
sequestration crisis, a splenectomy was performed when she was 2 years
old. Since that time, she had been asymptomatic and required no
transfusions in the previous 24 months. In a commentary on the work of
Geva et al. (2004), Benz (2004) noted that by itself, the L68F mutation
is known as hemoglobin Rockford, a member of a class of 'low affinity
hemoglobins' with reduced affinity for oxygen. These hemoglobins cause
few symptoms, if any. When the L68F and G6V mutations coexist in the
same beta-globin molecule, the L68F mutation causes Hb JP to desaturate
easily and therefore to sickle more readily than ordinarily occurs with
Hb S (G6V).

.0524
HEMOGLOBIN ROCKFORD
HBB, LEU68PHE

Perrault et al. (1997) described a low-affinity, stable hemoglobin
variant that did not result in hemolysis, which they designated Hb
Rockford; the variant is caused by a 335C-T transition in the HBB gene,
resulting in a leu68-to-phe (L68F) substitution. Geva et al. (2004)
described a hemoglobin variant with 2 amino acid substitutions, Hb
Rockford and Hb S (G6V; 141900.0243), which they designated Hb Jamaica
Plain (141900.0523).

.0525
HEMOGLOBIN TRIPOLI
HBB, GLU26ALA

In a 5-year-old boy of Libyan origin living in Tripoli, Libya, Lacan et
al. (2004) identified a change of codon 26 of the HBB gene from GAG
(glu) to GCG (ala) (glu26 to ala). They designated this hemoglobin
variant Hb Tripoli.

.0526
HEMOGLOBIN TIZI-OUZOU
HBB, GLY29SER

In a 66-year-old man born in Tizi-Ouzou in northeastern Algeria, Lacan
et al. (2004) described abnormal hemoglobin with change of codon 29 in
the first exon of the HBB gene from GGC (gly) to AGC (ser) (gly29 to
ser). The carrier showed hematologic abnormalities; the presence of
microcytosis and hypochromia was explained by an additional homozygous
3.7 kb alpha(+)-thalassemic deletion.

.0527
BETA-PLUS-THALASSEMIA
HBB, 3-UNT, T-A, +3

In a Tunisian patient with thalassemia intermedia (613985), Jacquette et
al. (2004) identified compound heterozygosity for mutations in the HBB
gene: a change from AATAAA to AAAAAA in the polyadenylation site of the
gene and a 2-bp insertion (25insTA) in codon 9 (141900.0528), causing a
frameshift with a premature termination at codon 19.

.0528
BETA-PLUS-THALASSEMIA
HBB, 2-BP INS, 25TA

See 141900.0527 and Jacquette et al. (2004).

.0529
BETA-PLUS-THALASSEMIA
HBB, 1-BP DEL, C

In 4 members of a Mexican family with beta-plus-thalassemia (613985),
Perea et al. (2004) identified heterozygosity for a 1-bp deletion (a
cytosine) in the HBB gene, resulting in a frameshift. The 1-bp deletion
was either in codon 77, changing CAC (his) to CA, or in codon 78,
changing CTG (leu) to TG.

.0530
BETA-PLUS-THALASSEMIA
HBB, -101C-G

The expression 'silent beta-thalassemia' (613985) is used to indicate a
group of thalassemia mutations that, in the heterozygous state, are
characterized by normal hematologic indices, normal or borderline HbA2
(141850) and HbF levels, and a slight imbalance of beta-globin chain
synthesis (Weatherall and Clegg, 2001). These mutations are usually
identified by genetic and molecular analysis of families in which a
proband is affected by thalassemia intermedia resulting from a compound
heterozygous state for a typical beta-thalassemia and silent
beta-thalassemia. One of the most common silent beta-thalassemia
mutations, described in several Mediterranean populations, is the C-to-T
substitution at position -101 in the distal CACCC box (141900.0370),
which leads to a moderate reduction of the expression level of the
beta-globin gene. In a silent beta-thalassemia carrier of Ashkenazi
Jewish descent, Moi et al. (2004) identified a C-to-G transversion at
the -101 position within the distal CACCC box of the HBB gene.

.0531
HEMOGLOBIN HOKUSETSU
HBB, ASP52GLY

During the assay of Hb A(1c) in a diabetic patient, Nakanishi et al.
(1998) identified a beta-chain variant: a change of codon 52 in exon 2
of the HBB gene from asp (GAT) to gly (GGT) (asp52 to gly). The patient
was hematologically normal.

.0532
HEMOGLOBIN KOCHI
HBB, LEU141VAL, LYS144TER

In a 53-year-old Japanese woman who underwent routine Hb A(1c) assay,
Miyazaki et al. (2005) identified 2 mutations in the same HBB gene:
codon 141 was changed from CTG (leu) to GTG (val) (L141V), and codon 144
was changed from AAG (lys) to TAG (stop) (K144X), leading to deletion of
the last 3 amino acids of the beta-globin chain, lys-tyr-his. The
increased oxygen affinity of the hemoglobin was consistent with the
presence of mild erythrocytosis.

.0533
HEMOGLOBIN ZOETERWOUDE
HBB, VAL23ALA

In a 77-year-old Dutch woman with erythrocytosis, Harteveld et al.
(2005) identified heterozygosity for a GTT-to-GCT transition at codon 23
of the HBB gene, causing a valine-to-alanine (V23A) amino acid change.
This was the fourth single-nucleotide substitution at codon 23 of the
HBB gene and the second that was associated with erythrocytosis.

.0534
HEMOGLOBIN BREM-SUR-MER
HBB, SER9TYR

In a 69-year-old man, Lacan et al. (2005) identified a TCT-to-TAT
transversion in codon 9 of the HBB gene, resulting in a ser9-to-tyr
(S9Y) amino acid change. No hematologic abnormalities were found. The
patient lived in the town of Brem-sur-Mer on the Atlantic coast of
France.

.0535
HEMOGLOBIN GELDROP ST. ANNA
HBB, ASP94TYR

Harteveld et al. (2005) observed an abnormal hemoglobin fraction during
an HPLC assay for Hb A(1c) control for diabetes mellitus in a
56-year-old northern European woman. This same abnormal fraction was
found in 3 of her 5 sibs and in her son. There was no history of anemia,
hemolytic, or circulatory episodes. Direct sequencing of the HBB gene
revealed a GAC-to-TAC transversion in heterozygous form at codon 94.
They concluded that the variant is a stable hemoglobin associated with a
slightly elevated oxygen affinity. Harteveld et al. (2005) noted that
this was the fourth mutation known to involve the asp94 residue of the
HBB gene; see 141900.0016, 141900.0035, and 141900.0045. A frameshift
mutation has also been reported at this position (141900.0338).

.0536
HEMOGLOBIN MARINEO
HBB, ALA70VAL

In a 3-generation family from western Sicily, Giambona et al. (2006)
identified heterozygosity for a GCC-GTC transition in the HBB gene,
resulting in an ala70-to-val (A70V) substitution. Three mutations at
codon 70 of the HBB gene had been previously described, all presenting
with hemolytic anemia. In the new case, no anemia or other alteration of
hematologic indices was found. The family lived in the town of Marineo
near Palermo, Sicily.

.0537
HEMOGLOBIN LA CORUNA
HBB, THR38ILE

Ropero et al. (2006) described Hb La Coruna, a novel hemoglobin variant
with increased oxygen affinity, leading to erythrocytosis. It is an
electrophoretically silent variant that can be detected by
reversed-phase high performance liquid chromatography (HPLC) and
characterized by DNA sequencing. The patient was a 22-year-old Spanish
male whose family lived in La Coruna in the northwest of Spain. The
mother was also a carrier.

.0538
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
DELTA/BETA THALESSEMIA, INCLUDED
HBB, 106-KB DEL

Kan et al. (1975) analyzed the DNA from a black patient with hereditary
persistence of fetal hemoglobin (141749) and found evidence for a
deletion of the beta-globin gene. Gallienne et al. (2009) cited several
reports in which patients with delta/beta thalassemia (see 141749) or
hereditary persistence of fetal hemoblobin had a 106-kb deletion of the
beta globin gene cluster. This mutation has been designated HPFH1.

.9999
HEMOGLOBIN BETA VARIANTS, MOLECULAR DEFECT UNKNOWN

HEMOGLOBIN CASERTA. Beta chain anomaly. See Ventruto et al. (1965) and
Quattrin et al. (1970).

HEMOGLOBIN D (FRANKFURT). Beta chain anomaly. See Martin et al. (1960)
and Gammack et al. (1961).

HEMOGLOBIN DURHAM-I (HEMOGLOBIN R). Beta chain anomaly. See Chernoff and
Weichselbaum (1958) and Chernoff and Pettit (1964).

HEMOGLOBIN J (JAMAICA). Beta chain anomaly. See Gammack et al. (1961).

HEMOGLOBIN K. Beta chain anomaly. See O'Gorman et al. (1963).

HEMOGLOBIN KINGS COUNTY. Probably beta chain defect. Observed in an
American black family. Affected persons had nonspherocytic hemolytic
Heinz body anemia. See Sathiapalan and Robinson (1968).

HEMOGLOBIN L. Beta chain anomaly. See Ager and Lehmann (1957) and
Gammack et al. (1961).

*FIELD* SA
Antonarakis et al. (1984); Antonarakis et al. (1982); Arous et al.
(1982); Bank et al. (1980); Barwick et al. (1985); Bernards et al.
(1979); Blackwell et al. (1971); Blackwell et al. (1972); Blackwell
et al. (1970); Blackwell et al. (1972); Blackwell et al. (1969); Blackwell
et al. (1970); Blackwell et al. (1969); Blackwell et al. (1969); Blouquit
et al. (1984); Boyer et al. (1963); Brennan et al. (1977); Cai et
al. (1989); Cai Yin Lin et al. (1982); Camaschella et al. (1987);
Cao et al. (1981); Chang et al. (1983); Chang and Kan (1979); Chang
and Kan (1982); Charache et al. (1977); Chen et al. (1985); Chifu
et al. (1992); Cole-Strauss et al. (1996); Collins et al. (1987);
Ding et al. (2004); Driscoll et al. (1981); Efstratiadis et al. (1980);
Enver et al. (1990); Forget (1979); Fritsch et al. (1980); Gacon
et al. (1977); Garel et al. (1976); Gilbert et al. (2000); Gonzalez-Redondo
et al. (1989); Gusella et al. (1979); Harano et al. (1985); Harano
et al. (1990); Harano et al. (1991); Harano et al. (1990); Harano
et al. (1990); Harano et al. (1983); Harano et al. (1981); Hebbel
et al. (1977); Heller et al. (1966); Honig et al. (1990); Horst et
al. (1983); Housman (1979); Idelson et al. (1974); Jeffreys and Flavell
(1977); Johnson et al. (1980); Jones et al. (1967); Kan et al. (1977);
Kan et al. (1975); Kan et al. (1980); Kaufman et al. (1980); Kohen
et al. (1982); Lacombe et al. (1987); Lawn et al. (1980); Lebo et
al. (1979); Li et al. (1990); Makhoul et al. (2005); Maniatis et al.
(1980); Miyaji et al. (1968); Molchanova et al. (1993); Moo-Penn et
al. (1977); Moo-Penn et al. (1976); Moo-Penn et al. (1977); Moo-Penn
et al. (1980); Moo-Penn et al. (1978); Nakatsuji et al. (1981); Necheles
et al. (1969); Novy et al. (1967); Ohba et al. (1983); Ohba et al.
(1989); Ohba et al. (1985); Ohba et al. (1975); Ohta et al. (1971);
Old et al. (1982); Orkin et al. (1978); Orkin et al. (1982); Orkin
et al. (1980); Orkin et al. (1982); Orkin et al. (1983); Ottolenghi
et al. (1976); Ottolenghi and Giglioni (1982); Ottolenghi et al. (1974);
Pirastu et al. (1984); Plaseska et al. (1991); Plaseska et al. (1991);
Plaseska et al. (1990); Prehu et al. (2002); Premawardhena et al.
(2005); Proudfoot et al. (1980); Rahbar et al. (1981); Ricco et al.
(1974); Rochette et al. (1984); Sanders-Haigh et al. (1980); Schiliro
et al. (1981); Schneider et al. (1969); Scott et al. (1979); Shibata
et al. (1961); Shibata et al. (1961); Smith and Conley (1959); Spritz
(1981); Studencki et al. (1985); Tamagnini et al. (1983); Taylor et
al. (1974); Tilghman et al. (1978); Tuan et al. (1985); Vella et al.
(1967); Verma and Edwards (1978); Villegas et al. (1989); Weatherall
and Clegg (1981); Williamson et al. (1983); Williamson et al. (1981);
Yoon et al. (1996); Zeng and Huang (1982); Zhao et al. (1990); Zinkham
et al. (1979)
*FIELD* RF
1. Abourzik, N. N.; Conlon, M.; Zordon, G.; Hine, T. K.; Johnson,
M. H.; Jue, D. L.; Moo-Penn, W. F.: Hb St. Francis [beta-121(GH4)glu-to-gly]:
a new mutation at the same site as Hb D-Los Angeles. Hemoglobin 15:
115-117, 1991.

2. Adachi, K.; Surrey, S.; Tamary, H.; Kim, J.; Eck, H. S.; Rappaport,
E.; Ohene-Frempong, K.: Hb Shelby [beta-131(H9)gln-to-lys] in association
with Hb S [beta-6(A3)glu-to-val]: characterization, stability, and
effects on Hb S polymerization. Hemoglobin 17: 329-343, 1993.

3. Adams, J. G.; Boxer, L. A.; Baehner, R. L.; Forget, B. G.; Tsistrokis,
G. A.; Steinberg, M. H.: Hemoglobin Indianapolis: post-translational
degradation of an unstable beta-chain variant producing a phenotype
of severe heterozygous beta-thalassemia. (Abstract) Clin. Res. 26:
501A, 1978.

4. Adams, J. G.; Heller, P.: Hemoglobin Arlington Park: a new hemoglobin
variant with two amino acid substitutions in the beta chain. Hemoglobin 1:
419-426, 1977.

5. Adams, J. G.; Smith, C. M.; Hedlund, B.; Olson, M.; Cich, J. A.;
Tukey, D. P.; Steinberg, M. H.: Hb North Shore: a hemoglobin variant
which produces the phenotype of beta(+)-thalassemia. (Abstract) Clin.
Res. 30: 499A, 1982.

6. Adams, J. G.; Steinberg, M. H.; Boxer, L. A.; Baehner, R. L.; Forget,
B. G.; Tsistrakis, G. A.: The structure of hemoglobin Indianapolis
(beta112(G14) arginine): an unstable variant detectable only by isotopic
labeling. J. Biol. Chem. 254: 3479-3482, 1979.

7. Adams, J. G., III; Morrison, W. T.; Pullen, D. J.; Abney, R. L.,
III; Steinberg, M. H.: Hemoglobin Mississippi (MS): a new hemoglobin
variant with three distinct electrophoretic mobilities. (Abstract) Clin.
Res. 33: 603A, 1985.

8. Adams, J. G., III; Przywara, K. P.; Heller, P.; Shamsuddin, M.
: Hemoglobin J Altgeld Gardens, a hemoglobin variant with a substitution
of the proximal histidine of the beta-chain. Hemoglobin 2: 403-415,
1978.

9. Adams, J. G., III; Przywara, K. P.; Shamsuddin, M.; Heller, P.
: Hemoglobin J Altgeld Gardens (beta 92 (F8) his-to-asp): a new hemoglobin
variant involving a substitution of the proximal histidine. (Abstract) Blood 46:
1029, 1975.

10. Adams, J. G., III; Steinberg, M. H.; Kazazian, H. H., Jr.: Isolation
and characterization of the translation product of a beta-globin gene
nonsense mutation (beta121 GAA-to-TAA). Brit. J. Haemat. 75: 561-567,
1990.

11. Adams, J. G., III; Steinberg, M. H.; Newman, M. V.; Morrison,
W. T.; Benz, E. J., Jr.; Iyer, R.: Beta-thalassemia present in cis
to a new beta-chain structural variant, Hb Vicksburg (beta-75(E19)leu-to-0). Proc.
Nat. Acad. Sci. 78: 469-473, 1981.

12. Adams, J. G., III; Winter, W. P.; Tausk, K.; Heller, P.: Hemoglobin
Rush (beta 101 (G-3) glu-to-gln): a new unstable hemoglobin causing
mild hemolytic anemia. Blood 43: 261-269, 1974.

13. Adamson, J. W.; Hayashi, A.; Stamatoyannopoulos, G.; Burger, W.
F.: Erythrocyte function and marrow regulation in hemoglobin Bethesda
(beta 145 histidine). J. Clin. Invest. 51: 2883-2888, 1972.

14. Adamson, J. W.; Parer, J. T.; Stamatoyannopoulos, G.: Erythrocytosis
associated with hemoglobin Rainier: oxygen equilibria and marrow regulation. J.
Clin. Invest. 48: 1376-1386, 1969.

15. Agarwal, A.; Guindo, A.; Cissoko, Y.; Taylor, J. G.; Coulibaly,
D.; Kone, A.; Kayentao, K.; Djimde, A.; Plowe, C. V.; Doumbo, O.;
Wellems, T. E.; Diallo, D.: Hemoglobin C associated with protection
from severe malaria in the Dogon of Mali, a West African population
with a low prevalence of hemoglobin S. Blood 96: 2358-2363, 2000.

16. Agarwal, S.; Hattori, Y.; Gupta, U. R.; Agarwal, S. S.: A novel
Indian beta-thalassemia mutation: Hb Lucknow (beta-8(A5)lys-to-arg). Hemoglobin 23:
263-265, 1999.

17. Ager, J. A. M.; Lehmann, H.: Haemoglobin L: a new haemoglobin
found in a Punjabi Hindu. Brit. Med. J. 2: 142-143, 1957.

18. Ager, J. A. M.; Lehmann, H.: Observations on some 'fast' haemoglobins:
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120. Blanke, S.; Johnsen, A.; Wimberley, P. D.; Mortensen, H. B.:
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121. Blibech, R.; Mrad, H.; Kastally, R.; Brissart, M. A.; Potron,
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123. Blouquit, Y.; Arous, N.; Lena, D.; Delanoe-Garin, J.; Lacombe,
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124. Blouquit, Y.; Arous, N.; Machado, P. E. A.; Garel, M. C.: Hb
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125. Blouquit, Y.; Bardakdjian, J.; Lena-Russo, D.; Arous, N.; Perrimond,
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128. Blouquit, Y.; Delanoe-Garin, J.; Lacombe, C.; Arous, N.; Cayre,
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150. Boyer, S. H.; Charache, S.; Fairbanks, V. F.; Maldonado, J. E.;
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151. Boyer, S. H.; Rucknagel, D. L.; Weatherall, D. J.; Watson-Williams,
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152. Brabec, V.; Indrak, K.; Fortova, H.; Suttnar, J.; Blazek, B.;
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159. Brennan, S. O.; Jones, K. O.; Crethar, L.; Arnold, B. J.; Fleming,
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160. Brennan, S. O.; Potter, H. C.; Kubala, L. M.; Carnoutsos, S.
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162. Brennan, S. O.; Wells, R. M.; Smith, H.; Carrell, R. W.: Hemoglobin
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163. Brennan, S. O.; Williamson, D.; Symmans, W. A.; Carrell, R. W.
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165. Brennan, S. O.; Williamson, D.; Whisson, M. E.; Carrell, R. W.
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166. Brimhall, B.; Jones, R. T.; Baur, E. W.; Motulsky, A. G.: Structural
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167. Brimhall, B.; Jones, T. T.; Schneider, R. G.; Hosty, T. S.; Tomlin,
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168. Brittenham, G.; Lozoff, B.; Harris, J. W.; Nayudu, N. V. S.;
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169. Bromberg, P. A.; Alben, J. O.; Bare, G. H.; Balcerzak, S. P.;
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170. Brown, W. J.; Niazi, G. A.; Jayalakshmi, M.; Abraham, E. C.;
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171. Broxson, E. H.; Hine, T. K.; Moo-Penn, W. F.: Hb Muskegon [beta-83
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172. Buckett, L. B.; Sharma, V. S.; Pisciotta, A. V.; Ranney, H.;
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173. Budge, L. J.; Bradley, T. B.; Graham, J. L.: Hemoglobin Riyadh
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174. Bundgaard, J. R.; Bjerrum, O. W.; Tybjaerg-Hansen, A.: A new
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176. Bunn, H. F.; Bradley, T. B.; Davis, W. E.; Drysdale, J. W.; Burke,
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177. Bunn, H. F.; Schmidt, G. J.; Haney, D. N.; Dluhy, R. G.: Hemoglobin
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178. Bursaux, E.; Blouquit, Y.; Poyart, C.; Rosa, J.; Arous, N.; Bohn,
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179. Butler, W. M.; Spratling, L.; Kark, J. A.; Schoomaker, E. B.
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181. Cai, S.-P.; Zhang, J.-Z.; Doherty, M.; Kan, Y. W.: A new TATA
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182. Cai, S. P.; Chang, C. A.; Zhang, J. Z.; Saiki, R. K.; Erlich,
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183. Cai Yin Lin; Wang He Be; Yang Xue Yong; Liu Zheng Hong; Ao Zhong
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184. Camaschella, C.; Bertero, M. T.; Serra, A.; Dall'Acqua, M.; Gasparini,
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185. Camaschella, C.; Serra, A.; Gottardi, E.; Alfarano, A.; Revello,
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186. Camaschella, C.; Serra, A.; Saglio, G.; Bertero, M. T.; Mazza,
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187. Cao, A.; Furbetta, M.; Galanello, R.; Melis, M. A.; Angius, A.;
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188. Carbone, V.; Salzano, A. M.; Pagano, L.; Buffardi, S.; De Rosa,
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189. Carbone, V.; Salzano, A. M.; Pagano, L.; Viola, A.; Buffardi,
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190. Carcassi, U. E. F.; Pintus, A.; Gravely, M. E.; Huisman, T. H.
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193. Carrell, R. W.; Lehmann, H.; Lorkin, P. A.; Raik, E.; Hunter,
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197. Castagnola, M.; Cassiano, L.; Rossetti, D. V.; Marucci, L.; Ferro,
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202. Chan, V.; Chan, T. K.; Kan, Y. W.; Todd, D.: A novel beta-thalassemia
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203. Chang, J.-G.; Lee, L.-S.; Chen, P.-H.; Chen, Y.-H.: Hb Kaohsiung
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213. Charache, S.; Achuff, S.; Winslow, R.; Kazazian, H.: Oxygen
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215. Charache, S.; Brimhall, B.; Milner, P.; Cobb, L.: Hemoglobin
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216. Charache, S.; Fox, J.; McCurdy, P.; Kazazian, H., Jr.; Winslow,
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217. Charache, S.; Jacobson, R.; Brimhall, B.; Murphy, E. A.; Hathaway,
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218. Charache, S.; Zinkham, W. H.; Dickerman, J. D.; Brimhall, B.;
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219. Chebloune, Y.; Pagnier, J.; Trabuchet, G.; Faure, C.; Verdier,
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220. Chehab, F. F.; Honig, G. R.; Kan, Y. W.: Spontaneous mutation
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222. Chen, S. S.; Webber, B. B.; Wilson, J. B.; Huisman, T. H. J.
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223. Chen, S. S.; Wilson, J. B.; Webber, B. B.; Kutlar, A.; Huisman,
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517. Itano, H. A.; Neel, J. V.: A new inherited abnormality of human
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519. Iuchi, I.; Shimasaki, S.; Hidaka, K.; Ueda, S.; Harano, T.; Shibata,
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520. Iuchi, I.; Ueda, S.; Hidaka, K.; Shibata, S.: Hemoglobin Hoshida
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521. Ivaldi, G.; David, O.; Baffico, M.; Leone, D.; Baldi, M.; Parodi,
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525. Jackson, J. M.; Yates, A.; Huehns, E. R.: Haemoglobin Perth:
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526. Jacquette, A.; Le Roux, G.; Lacombe, C.; Goossens, M.; Pissard,
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527. Jankovic, L.; Dimovski, A. J.; Sukarova, E.; Juricic, D.; Efremov,
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528. Jankovic, L.; Efremov, G. D.; Josifovska, O.; Juricic, D.; Stoming,
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530. Jeffreys, A. J.; Flavell, R. A.: The rabbit beta-globin gene
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531. Jensen, M.; Oski, F. A.; Nathan, D. G.; Bunn, H. F.: Hemoglobin
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532. Jeppsson, J. O.; Kallman, L.; Lindgren, G.; Fagerstam, L. G.
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533. Johnson, C. S.; Moyes, D.; Schroeder, W. A.; Shelton, J. B.;
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534. Johnson, M. H.; Jue, D. L.; Patchen, L. C.; Hartwig, E. C., Jr.;
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535. Jones, R. T.; Brimhall, B.; Gray, G.: Hemoglobin British Columbia
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536. Jones, R. T.; Brimhall, B.; Huehns, E. R.; Motulsky, A. G.:
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537. Jones, R. T.; Brimhall, B.; Huisman, T. H. J.; Kleihauer, E.;
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538. Jones, R. T.; Brimhall, B.; Pootrakul, S.; Gray, G.: Hemoglobin
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539. Jones, R. T.; Grimes, A. J.; Carrell, R. W.; Lehmann, H.: Koln
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540. Jones, R. T.; Head, C.; Shih, M. F.-C.; Shih, D. T.-B.; Dana,
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543. Jones, R. T.; Osgood, E. E.; Brimhall, B.; Koler, R. D.: Hemoglobin
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544. Jones, R. T.; Saiontz, H. I.; Head, C.; Shih, D. T. B.; Fairbanks,
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545. Josephson, A. M.; Weinstein, H. G.; Yakulis, V. J.; Singer, L.;
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546. Juricic, D.; Ruzdic, I.; Beer, Z.; Efremov, G. D.; Casey, R.;
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547. Kagimoto, T.; Morino, Y.; Kishimoto, S.: A new hemoglobin variant,
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548. Kalberer, C. P.; Pawliuk, R.; Imren, S.; Bachelot, T.; Takekoshi,
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555. Kan, Y. W.; Golbus, M. S.; Trecartin, R.: Prenatal diagnosis
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557. Kan, Y. W.; Holland, J. P.; Dozy, A. M.; Varmus, H. E.: Demonstration
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558. Kan, Y. W.; Lee, K. Y.; Forbetta, M.; Angius, A.; Cao, A.: Polymorphism
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559. Kaplan, F.; Kokotsis, G.; DeBraekeleer, M.; Morgan, K.; Scriver,
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560. Kattamis, A. C.; Kelly, K. M.; Ohene-Frempong, K.; Reilly, M.
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562. Kaufman, S.; Leiba, H.; Clejan, L.; Wallis, K.; Lorkin, P. A.;
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563. Kavanaugh, J. S.; Rogers, P. H.; Case, D. A.; Arnone, A.: High-resolution
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564. Kawata, R.; Ohba, Y.; Fujisawa, K.; Miyaji, T.; Tani, Y.; Iwasaki,
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565. Kawata, R.; Ohba, Y.; Yamamoto, K.; Miyaji, T.; Makita, R.; Ohga,
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566. Kazazian, H. H., Jr.: Personal Communication. Baltimore, Md.
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567. Kazazian, H. H., Jr.: Personal Communication. Baltimore, Md.
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568. Kazazian, H. H., Jr.: Personal Communication. Baltimore, Md.
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569. Kazazian, H. H., Jr.: Personal Communication. Baltimore, Md.
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570. Kazazian, H. H., Jr.; Boehm, C. D.: Molecular basis and prenatal
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571. Kazazian, H. H., Jr.; Dowling, C. E.; Hurwitz, R. L.; Coleman,
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572. Kazazian, H. H., Jr.; Dowling, C. E.; Hurwitz, R. L.; Coleman,
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573. Kazazian, H. H., Jr.; Fearon, E. R.; Waber, P. G.; Lee, J. I.;
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574. Kazazian, H. H., Jr.; Orkin, S. H.; Antonarakis, S. E.; Sexton,
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575. Kazazian, H. H., Jr.; Orkin, S. H.; Boehm, C. D.; Goff, S. C.;
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576. Kazazian, H. H., Jr.; Orkin, S. H.; Boehm, C. D.; Sexton, J.
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577. Kazazian, H. H., Jr.; Waber, P. G.; Boehm, C. D.; Lee, J. I.;
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578. Keclard, L.; Campier, A.; Merault, G.; Auperin, A.; Riou, J.;
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579. Keeling, M. M.; Bertolone, S. J.; Baysal, E.; Gu, Y.-C.; Cepreganova,
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580. Keeling, M. M.; Ogden, L. L.; Wrightstone, R. N.; Wilson, J.
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581. Kendall, A.; Pang, W.: Hemoglobin New York associated with alpha-thalassemia. Hum.
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582. Kendall, A.; Young, S.; Oune, N.; Wiltshire, B.; Lehmann, H.
: The unstable Hb Genova (beta 28 leu-to-pro) in a East African family:
family study and the effect of splenectomy. Acta Haemat. 61: 278-282,
1979.

583. Kendall, A. G.; ten Pas, A.; Wilson, J. B.; Cope, N.; Bolch,
K.; Huisman, T. H. J.: Hb Vaasa or beta 39: gln-to-glu, a mildly
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584. Kennedy, C. C.; Blundell, G.; Lorkin, P. A.; Lang, A.; Lehmann,
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585. Keser, I.; Kayisli, O. G.; Yesilipek, A.; Ozes, O. N.; Luleci,
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unstable variant leading to chronic microcytic anemia and high Hb
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586. Kiger, L.; Kister, J.; Groff, P.; Kalmes, G.; Prome, D.; Galacteros,
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binding properties in a new variant involving a residue located distal
to the heme. Hemoglobin 20: 135-140, 1996.

587. Kim, J. Y.; Park, S. S.; Jung, H. L.; Keum, D. H.; Park, H.;
Chang, Y. H.; Lee, Y. J.; Cho, H. I.: Hb Madrid (beta-115(G17)ala-to-pro)
in a Korean family with chronic hemolytic anemia. Hemoglobin 24:
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588. Kim, J. Y.; Park, S. S.; Yang, S. H.; Joo, S.-I.; Lee, Y. J.;
Ra, E. K.; Shin, S.; Kim, E. C.; Cho, H.-I.: A Korean family with
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589. Kimura, A.; Matsunaga, E.; Takihara, Y.; Nakamura, T.; Takagi,
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590. Kimura, A.; Ohta, Y.; Fukumaki, Y.; Takagi, Y.: A fusion gene
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591. Kimura, E. M.; Jorge, S. B.; Ogo, S. H.; Cesquini, M.; Albuquerque,
D. M.; Fattori, A.; Saad, S. T. O.; Costa, F. F.; Sonati, M. F.:
A novel beta-globin variant: Hb Pocos de Caldas (beta-61(E5)lys-to-gln). Hemoglobin 26:
385-388, 2002.

592. King, M. A. R.; Wiltshire, B. G.; Lehmann, H.; Morimoto, H.:
An unstable haemoglobin with reduced oxygen affinity: haemoglobin
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with normal haemoglobin and with haemoglobin Lepore. Brit. J. Haemat. 22:
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593. Kinniburgh, A. J.; Maquat, L. E.; Schedl, T.; Rachmilewitz, E.;
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594. Kister, J.; Prehu, C.; Riou, J.; Godart, C.; Bardakdjian, J.;
Prome, D.; Galacteros, F.; Wajcman, H.: Two hemoglobin variants with
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21-32, 1999.

595. Kleckner, H. B.; Wilson, J. B.; Lindeman, J. G.; Stevens, P.
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Fort Gordon (beta 145 tyr-to-asp), a new high-oxygen-affinity hemoglobin
variant. Biochim. Biophys. Acta 400: 343-347, 1975.

596. Kobayashi, S.; Nara, T.; Nakano, Y.; Fukazawa, H.; Kawamura,
G.; Kitajima, H.; Sugita, M.; Joh, K.; Ohba, Y.; Hattori, Y.; Miyaji,
T.: Hemoglobin Burke: an unstable hemoglobin rarely associated with
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597. Kobayashi, Y.; Fukumaki, Y.; Komatsu, N.; Ohba, Y.; Miyaji, T.;
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leu-to-pro) causing a beta-thalassemia phenotype. Blood 70: 1688-1691,
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598. Kohen, G.; Philippe, N.; Godet, J.: Polymorphism of the HindI
restriction site located 1 kb 5-prime to the human beta-globin gene. Hum.
Genet. 62: 121-123, 1982.

599. Kohne, E.; Grosse, H. P.; Versmold, H.; Kley, H. P.; Kleihauer,
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und Diaphorasemangel. Z. Kinderheilk. 120: 69-78, 1975.

600. Kohne, E.; Kley, H. P.; Kleihauer, E.: Structural and functional
characteristics of the Hb Tubingen: beta 106 (G8) leu-to-gln. FEBS
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601. Kohne, E.; Wendt, F.-K.; Kleinhauer, E.: Hb M Milwaukee in a
German family. Hemoglobin 1: 759-769, 1977.

602. Koler, R. D.; Jones, R. T.; Bigley, R. H.; Litt, M.; Lovrien,
E.; Brooks, R.; Lahey, M. E.; Fowler, R.: Hemoglobin Casper: beta
106 (gamma 8) leu-to-pro: a contemporary mutation. Am. J. Med. 55:
549-558, 1973.

603. Kollia, P.; Gonzalez-Redondo, J. M.; Stoming, T. A.; Loukopoulos,
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604. Konotey-Ahulu, F. I. D.; Gallo, E.; Lehmann, H.; Ringelhann,
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605. Konotey-Ahulu, F. I. D.; Kinderlerer, J. L.; Lehmann, H.; Ringelhann,
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606. Koop, B. F.; Goodman, M.; Xu, P.; Chan, K.; Slightom, J. L.:
Primate eta-globin DNA sequences and man's place among the great apes. Nature 319:
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607. Kosugi, H.; Weinstein, A. S.; Kikugawa, K.; Asakura, T.: Characterization
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608. Krawczak, M.; Ball, E. V.; Fenton, I.; Stenson, P. D.; Abeysinghe,
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609. Krawczak, M.; Reiss, J.; Cooper, D. N.: The mutational spectrum
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610. Krishnan, K.; Martinez, F.; Cooney, K.; Jones, R. T.; Shih, D.
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611. Krishnan, K.; Martinez, F.; Wille, R. T.; Jones, R. T.; Shih,
D. T.; Head, C.; Fairbanks, V. F.; Dabich, L.: Hb Washtenaw (beta-11(A8)
val-to-phe): an electrophoretically silent, unstable, low oxygen affinity
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612. Kuis-Reerink, J. D.; Jonxis, J. H.; Niazi, G. A.; Wilson, J.
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beta-2 27(B9) ala replaced by asp: an unstable hemoglobin variant
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613. Kulozik, A. E.; Wainscoat, J. S.; Serjeant, G. R.; Kar, B. C.;
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614. Kulozik, A. E.; Yarwood, N.; Jones, R. W.: The Corfu delta-beta-zero
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711. Metherall, J. E.; Collins, F. S.; Pan, J.; Weissman, S. M.; Forget,
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712. Millar, C. M.; Phelan, L.; Bain, B. J.: Diabetes mellitus diagnosed
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713. Miller, D. R.; Smetanina, N. S.; Gu, L.-H.; Leonova, J. Y.; Huisman,
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714. Miller, D. R.; Weed, R. I.; Stamatoyannopoulos, G.; Yoshida,
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715. Miller, D. R.; Wilson, J. B.; Kutlar, A.; Huisman, T. H. J.:
Hb Bicetre or beta63(E7)his-to-pro in a white male: clinical observations
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716. Miller, H. I.; Konkel, D. A.; Leder, P.: An intervening sequence
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717. Milner, P. F.: High incidence of hemoglobin G (Accra) in a rural
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718. Milner, P. F.; Corley, C. C.; Pomeroy, W. L.; Wilson, J. B.;
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719. Milner, P. F.; Miller, C.; Grey, R.; Seakins, M.; De Jong, W.
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720. Minnich, V.; Hill, R. J.; Khuri, P. D.; Anderson, M. E.: Hemoglobin
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721. Miranda, S. R. P.; Kimura, E. M.; Saad, S. T. O.; Costa, F. F.
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722. Miranda, S. R. P.; Kimura, E. M.; Teixeira, R. C.; Bertuzzo,
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723. Miyaji, T.; Ohba, Y.; Matsuoka, M.; Kudoh, H.; Asano, M.; Yamamoto,
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724. Miyaji, T.; Ohba, Y.; Yamamoto, K.; Shibata, S.; Iuchi, I.; Hamilton,
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725. Miyaji, T.; Ohba, Y.; Yamamoto, K.; Shibata, S.; Iuchi, I.; Takenaka,
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726. Miyaji, T.; Suzuki, H.; Ohba, Y.; Shibata, S.: Hemoglobin Agenogi
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727. Miyazaki, A.; Nakanishi, T.; Kishikawa, M.; Nakagawa, T.; Shimizu,
A.; Mawjood, A. H. M.; Imai, K.; Aoki, Y.; Kikuchi, M.: Compound
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728. Miyazaki, A.; Nakanishi, T.; Shimizu, A.; Mizobuchi, M.; Yamada,
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(g.1413A-T)): a new variant with increased oxygen affinity. Hemoglobin 29:
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729. Miyazaki, A.; Nakanishi, T.; Shimizu, A.; Ninomiya, K.; Nishimura,
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730. Modell, B.; Darlison, M.: Global epidemiology of haemoglobin
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731. Modiano, D.; Bancone, G.; Ciminelli, B. M.; Pompei, F.; Blot,
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732. Modiano, D.; Luoni, G.; Sirima, B. S.; Simpore, J.; Verra, F.;
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733. Moghimi, B.; Yavarian, M.; Oberkanins, C.; Amini, S. S. H.; Khatami,
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734. Moi, P.; Faa, V.; Marini, M. G.; Asunis, I.; Ibba, G.; Cao, A.;
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735. Molchanova, T. P.; Postnikov, Y. V.; Gu, L.-H.; Huisman, T. H.
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736. Molchanova, T. P.; Postnikov, Y. V.; Gu, L.-H.; Prior, J. F.;
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737. Molchanova, T. P.; Postnikov, Y. V.; Pobedimskaya, D. D.; Smetanina,
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738. Molchanova, T. P.; Wilson, J. B.; Gu, L.-H.; Guemira, F.; Fattoum,
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739. Monn, E.; Gaffney, P. J.; Lehmann, H.: Haemoglobin Sogn (beta
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740. Monplaisir, N.; Merault, G.; Poyart, C.; Rhoda, M.-D.; Craescu,
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741. Moo-Penn, W. F.: Personal Communication. Atlanta, Ga. 1981.

742. Moo-Penn, W. F.; Bechtel, K. C.; Johnson, M. H.; Jue, D. L.;
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743. Moo-Penn, W. F.; Bechtel, K. C.; Schmidt, R. M.; Johnson, M.
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744. Moo-Penn, W. F.; Hine, T. K.; Johnson, M. H.; Jue, D. L.; Holland,
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745. Moo-Penn, W. F.; Johnson, M. H.; Bechtel, K. C.; Jue, D. L.;
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746. Moo-Penn, W. F.; Johnson, M. H.; Jue, D. L.; Lonser, R.: Hb
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747. Moo-Penn, W. F.; Johnson, M. H.; McGuffey, J. E.; Jue, D. L.
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748. Moo-Penn, W. F.; Johnson, M. H.; McGuffey, J. E.; Jue, D. L.;
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749. Moo-Penn, W. F.; Jue, D. L.; Bechtel, K. C.; Johnson, M. H.;
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750. Moo-Penn, W. F.; Jue, D. L.; Bechtel, K. C.; Johnson, M. H.;
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751. Moo-Penn, W. F.; Jue, D. L.; Johnson, M. H.; Bechtel, K. C.;
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752. Moo-Penn, W. F.; Jue, D. L.; Johnson, M. H.; Olsen, K. W.; Shih,
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753. Moo-Penn, W. F.; McGuffey, J. E.; Jue, D. L.; Johnson, M. H.;
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754. Moo-Penn, W. F.; Schmidt, R. M.; Jue, D. L.; Bechtel, K. C.;
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755. Moo-Penn, W. F.; Schneider, R. G.; Andrian, S.; Das, D. K.:
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756. Moo-Penn, W. F.; Schneider, R. G.; Shih, T.; Jones, R. T.; Govindarajan,
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757. Moo-Penn, W. F.; Wolff, J. A.; Simon, G.; Vacek, M.; Jue, D.
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760. Mrad, A.; Blouquit, Y.; Lacombe, C.; Blibech, R.; Arous, N.;
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761. Muller, C. J.; Kingma, S.: Haemoglobin Zurich beta 63 arg. Biochim.
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762. Murawski, K.; Carta, S.; Sorcini, M.; Tentori, L.; Vivaldi, G.;
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763. Murru, S.; Loudianos, G.; Deiana, M.; Camaschella, C.; Sciarratta,
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764. Murru, S.; Pischedda, M. C.; Cao, A.; Rosatelli, M. C.; Pirastu,
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767. Nagel, R. L.; Daar, S.; Romero, J. R.; Suzuka, S. M.; Gravell,
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768. Nagel, R. L.; Fabry, M. E.; Pagnier, J.; Zohoun, I.; Wajcman,
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769. Nagel, R. L.; Lin, M. J.; Witkowska, H. E.; Fabry, M. E.; Bestak,
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770. Nagel, R. L.; Lynfield, J.; Johnson, J.; Landau, L.; Bookchin,
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771. Nakamura, T.; Araki, M.; Kuzuo, Y.; Harano, T.; Harano, K.; Ohba,
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772. Nakanishi, T.; Miyazaki, A.; Kishikawa, M.; Shimizu, A.; Aoki,
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773. Nakanishi, T.; Miyazaki, A.; Kishikawa, M.; Shimizu, A.; Kishida,
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774. Nakatsuji, T.; Miwa, S.; Ohba, Y.; Hattori, Y.; Miyaji, T.; Hino,
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775. Nakatsuji, T.; Miwa, S.; Ohba, Y.; Hattori, Y.; Miyaji, T.; Miyata,
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(B5) val-to-gly): an electrophoretically silent variant discovered
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776. Naritomi, Y.; Naito, Y.; Nakashima, H.; Yokota, E.; Imamura,
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777. Navas, P. A.; Li, Q.; Peterson, K. R.; Swank, R. A.; Rohde, A.;
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779. Necheles, T. F.; Allen, D. M.; Gerald, P. S.: The many forms
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780. Neel, J. V.: The inheritance of sickle cell anemia. Science 110:
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781. Neel, J. V.; Kaplan, E.; Zuelzer, W. W.: Further studies of
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782. Negri Arjona, S.; Eloy-Garcia, J. M.; Gu, L.-H.; Smetanina, N.
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783. Negri Arjona, S.; Maldonado Eloy-Garcia, J.; Molchanova, T. P.;
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784. Ngiwsara, L.; Srisomsap, C.; Winichagoon, P.; Fucharoen, S.;
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787. North, M. L.; Duwig, I.; Riou, J.; Prome, D.; Yapo, A. P.; Kister,
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790. Nute, P. E.; Stamatoyannopoulos, G.; Hermodson, M. A.; Roth,
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791. O'Donnell, A.; Premawardhena, A.; Arambepola, M.; Samaranayake,
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792. O'Gorman, P.; Lehmann, H.; Allsopp, K. M.; Sukumaran, P. K.:
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794. Oehme, R.; Kohne, E.; Kleihauer, E.; Horst, J.: Hb M Milwaukee:
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795. Ogata, K.; Ito, T.; Okazaki, T.; Dan, K.; Nomura, T.; Nozawa,
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796. Ohashi, J.; Naka, I.; Patarapotikul, J.; Hananantachai, H.; Brittenham,
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799. Ohba, Y.; Hattori, Y.; Ami, M.; Yagami, H.; Miyaji, T.; Tani,
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found in Japan. Hemoglobin 14: 109-114, 1990.

800. Ohba, Y.; Hattori, Y.; Fuyuno, K.; Takeda, I.; Matsuoka, M.;
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Hirose, beta37 (C3) trp-to-ser. Hemoglobin 7: 191-193, 1983.

801. Ohba, Y.; Hattori, Y.; Miyaji, T.; Takasaki, M.; Shirahama, M.;
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802. Ohba, Y.; Hattori, Y.; Sakata, S.; Yamashiro, Y.; Okayama, N.;
Hirano, T.; Nakanishi, T.; Miyazaki, A.; Shimizu, A.: Hb Niigata
[beta-1(NA1)val-to-leu]: the fifth variant with retention of the initiator
methionine and partial acetylation. Hemoglobin 21: 179-186, 1997.

803. Ohba, Y.; Imai, K.; Kumada, I.; Ohsawa, A.; Miyaji, T.: Hb Moriguchi
or beta97(FG4)his-to-tyr substitution at the alpha(1)-beta(2) interface. Hemoglobin 13:
367-376, 1989.

804. Ohba, Y.; Imanaka, M.; Matsuoka, M.; Hattori, Y.; Miyaji, T.;
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a new hemoglobin mutant with increased oxygen affinity and lowered
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903. Qin, W.-B.; Pobedimskaya, D. D.; Molchanova, T. P.; Wilson, J.
B.; Gu, L.-H.; de Pablos, J. M.; Huisman, T. H. J.: Hb Fannin-Lubbock
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904. Qualtieri, A.; Le Pera, M.; Pedace, V.; Magariello, A.; Brancati,
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neutral beta chain variant found in an Italian woman. Hemoglobin 26:
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905. Quarum, M.; Shih, T.; Jones, R. T.: Oxygen equilibrium studies
of Hb Willamette, beta51(D2)pro-to-arg. Hemoglobin 7: 57-69, 1983.

906. Quattrin, N.; Ventruto, V.; De Rosa, L.: Hemoglobinopathies
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907. Ragusa, A.; Lombardo, M.; Sortino, G.; Lombardo, T.; Nagel, R.
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908. Rahbar, S.: Haemoglobin D Iran: beta 22 glutamic acid to glutamine
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909. Rahbar, S.; Asmerom, Y.; Blume, K. G.: A silent hemoglobin variant
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333-342, 1984.

910. Rahbar, S.; Beale, D.; Isaacs, W. A.; Lehmann, H.: Abnormal
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911. Rahbar, S.; Feagler, R. J.; Beutler, E.: Hemoglobin Hammersmith,
beta 42 (CD1) phe-to-ser, associated with severe hemolytic anemia. Hemoglobin 5:
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912. Rahbar, S.; Lee, T.; Asmeron, Y.: Hb Beckman alpha135 (H13)
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913. Rahbar, S.; Louis, J.; Lee, T.; Asmerom, Y.: Hemoglobin North
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914. Rahbar, S.; Nowzari, G.; Ala, F.: Haemoglobin Avicenna (beta47
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915. Rahbar, S.; Nowzari, G.; Haydari, H.; Kaneshmand, P.: Hemoglobin
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916. Rahbar, S.; Rea, C.; Blume, K.; Seltzer, D.; Feiner, R.: A second
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917. Rahbar, S.; Rosen, R.; Nozari, G.; Lee, T. D.; Asmerom, Y.; Wallace,
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918. Rahbar, S.; Winkler, K.; Louis, J.; Rea, C.; Blume, K.; Beutler,
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919. Ramachandran, M.; Gu, L.-H.; Wilson, J. B.; Kitundu, M. N.; Adekile,
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920. Ramot, B.; Fisher, S.; Remez, D.; Schneerson, R.; Kahane, D.;
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921. Ramsay, M.; Jenkins, T.: Globin gene--associated restriction-fragment-length
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922. Ranney, H. M.; Jacobs, A. S.; Nagel, R. L.: Haemoglobin New
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923. Ranney, H. M.; Jacobs, A. S.; Udem, L.; Zalusky, R.: Hemoglobin
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924. Ranney, H. M.; Larson, D. L.; McCormack, G. H., Jr.: Some clinical,
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925. Reed, C. S.; Hampson, R.; Gordon, S.; Jones, R. T.; Novy, M.
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926. Rees, D. C.; Duley, J.; Simmonds, H. A.; Wonke, B.; Thein, S.
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929. Ren, Y.; Chen, S. S.; Liang, C. C.; Zhang, M. J.; Huang, M. X.;
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930. Renda, M.; Maggio, A.; Warren, T. C.; Kazazian, H. H., Jr.:
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931. Rey, K. S.; Unger, C. A.; Rao, S. P.; Miller, S. T.: Sickle
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932. Ribeiro, M. L. S.; Baysal, E.; Kutlar, F.; Tamagnini, G. P.;
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933. Ricco, G.; Gallo, E.; Pich, P. G.; Miniero, R.; Mazza, U.: Haemoglobin
G San Jose in an Italian family. Acta Haemat. 52: 180-188, 1974.

934. Ricco, G.; Pich, P. G.; Mazza, U.; Rossi, G.; Ajmar, F.; Arese,
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935. Rieder, R. F.; Bradley, T. B., Jr.: Hemoglobin Gun Hill: an
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936. Rieder, R. F.; Oski, F. A.; Clegg, J. B.: Hemoglobin Philly
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937. Rieder, R. F.; Wolf, D. J.; Clegg, J. B.; Lee, S. L.: Hemoglobin
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938. Rieder, R. F.; Zinkham, W. H.; Holtzman, N. A.: Hemoglobin Zurich:
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939. Rihet, P.; Flori, L.; Tall, F.; Traore, A. S.; Fumoux, F.: Hemoglobin
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940. Ringelhann, B.; Konotey-Ahulu, F. I. D.; Talapatra, N. C.; Nkrumah,
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941. Ristaldi, M. S.; Murru, S.; Loudianos, G.; Casula, L.; Porcu,
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942. River, G. L.; Robbins, A. B.; Schwartz, S. O.: S-C hemoglobin:
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943. Rochette, J.; Boissel, J. P.; Labie, D.; Wajcman, H.; Poyart,
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944. Rochette, J.; Poyart, C.; Varet, B.; Wajcman, H.: A new hemoglobin
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945. Rodrigues de Souza, L.; Kimura, E. M.; Albuquerque, D. M.; Costa,
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946. Rodriguez Romero, W. E.; Castillo, M.; Chaves, M. A.; Saenz,
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947. Rohe, R. A.; Sharma, V. S.; Ranney, H. M.: Double heterozygosity
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948. Romain, P. L.; Schwartz, A. D.; Shamsuddin, M.; Adams, J. G.,
III; Mason, R. G.; Vida, L. N.; Honig, G. R.: Hemoglobin J (Chicago)
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949. Romero, C.; Fernandez Fuertes, I.; Quintana, A.; Blanco, L.;
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950. Romero, J. R.; Suzuka, S. M.; Nagel, R. L.; Fabry, M. E.: Arginine
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951. Romey, M.-C.; Aguilar-Martinez, P.; Demaille, J.; Claustres,
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952. Rooks, H.; Bergounioux, J.; Game, L.; Close, J. P.; Osborne,
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953. Ropero, P.; Fernandez-Lago, C.; Villegas, A.; Polo, M.; Mateo,
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954. Rosa, J.; Labie, D.; Wajcman, H.; Boigne, J. M.; Cabannes, R.;
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955. Rosatelli, C.; Leoni, G. B.; Tuveri, T.; Scalas, M. T.; Di Tucci,
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956. Rosatelli, M. C.; Dozy, A.; Faa, V.; Meloni, A.; Sardu, R.; Saba,
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957. Rotoli, B.; Camera, A.; Fontana, R.; Frigeri, F.; Pandolfi, G.;
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958. Rouabhi, F.; Chardin, P.; Boissel, J. P.; Beghoul, F.; Labie,
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959. Rousseaux, J.; Nuyts, J. P.; Demouveau, G.; Deutrevaux, M.:
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960. Rucknagel, D. L.: Personal Communication. Ann. Rev. Med.
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961. Rucknagel, D. L.: Personal Communication. Cincinnati, Ohio
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962. Rund, D.; Cohen, T.; Filon, D.; Dowling, C. E.; Warren, T. C.;
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963. Rund, D.; Dowling, C.; Najjar, K.; Rachmilewitz, E. A.; Kazazian,
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964. Rund, D.; Filon, D.; Rachmilewitz, E. A.; Cohen, T.; Dowling,
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965. Ruvidic, R.; Efremov, G. D.; Juricic, D.; Rolovic, Z.; Pendic,
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966. Ryrie, D. R.; Plowman, D.; Lehmann, H.: Haemoglobin Sherwood
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967. Saba, L.; Meloni, A.; Sardu, R.; Travi, M.; Primignani, P.; Rosatelli,
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968. Saenz, G. F.; Arroyo, G.; Montero, G.; Lima, F.; Martinez, G.;
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969. Saglio, G.; Camaschella, C.; Serra, A.; Bertero, T.; Cambrin,
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970. Saiki, R. K.; Bugawan, T. L.; Horn, G. T.; Mullis, K. B.; Erlich,
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971. Salhany, J. M.: The deoxygenation kinetics of hemoglobin Rainier
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972. Salomon, H.; Tatarski, I.; Dance, N.; Huehns, E. R.; Shooter,
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973. Salzano, A. M.; Carbone, V.; Pagano, L.; Buffardi, S.; De Rosa,
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977. Sansone, G.; Carrell, R. W.; Lehmann, H.: Haemoglobin Genova:
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978. Sansone, G.; Sciarratta, G. V.; Genova, R.; Darbre, P. D.; Lehmann,
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979. Sathiapalan, R.; Robinson, M. G.: Hereditary haemolytic anaemia
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980. Schiliro, G.; Li Volti, S.; Musumeci, S.; Mollica, F.; Marinucci,
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981. Schiliro, G.; Musumeci, S.; Russo, A.; Marino, S.; Russo, G.;
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982. Schiliro, G.; Russo-Mancuso, G.; Dibenedetto, S. P.; Samperi,
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983. Schmidt, R. M.; Bechtel, K. C.; Johnson, M. H.; Therrell, B.
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984. Schmidt, R. M.; Jue, D. L.; Lyonnais, J.; Moo-Penn, W. F.: Hemoglobin
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985. Schnee, J.; Aulehla-Scholz, C.; Eigel, A.; Horst, J.: Hb D Los
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986. Schnee, J.; Griese, E. U.; Eigel, A.; Horst, J.: Beta-thalassemia
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987. Schneider, R.: Personal Communication. Galveston, Tex. 10/6/1978.

988. Schneider, R. G.; Alperin, J. B.; Brimhall, B.; Jones, R. T.
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989. Schneider, R. G.; Bremner, J. E.; Brimhall, B.; Jones, R. T.;
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990. Schneider, R. G.; Haggard, M. E.; McNutt, C. W.; Johnson, J.
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991. Schneider, R. G.; Hethig, R. A.; Bilunos, M.; Brimhall, B.:
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992. Schneider, R. G.; Hosty, T. S.; Tomlin, G.; Atkins, R.; Brimhall,
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993. Schneider, R. G.; Ueda, S.; Alperin, J. B.; Brimhall, B.; Jones,
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994. Schneider, R. G.; Ueda, S.; Alperin, J. B.; Levin, W. C.; Jones,
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995. Schoenfelder, S.; Sexton, T.; Chakalova, L.; Cope, N. F.; Horton,
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997. Schroeder, W. A.; Powars, D.; Shelton, J. B.; Shelton, J. R.;
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998. Schwartz, H. C.; Spaet, T. H.; Zuelzer, W. W.; Neel, J. V.; Robinson,
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999. Sciarratta, G. V.; Ivaldi, G.: Hb Matera (beta55(D6)met-to-lys):
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1000. Sciarratta, G. V.; Ivaldi, G.; Moruzzi, F.: Hb J-Guantanamo
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1001. Sciarratta, G. V.; Ivaldi, G.; Sansone, G.; Wilson, J. B.; Webber,
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1002. Scott, A. F.; Phillips, J. A., III; Migeon, B. R.: DNA restriction
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1003. Seid-Akhavan, M.; Ayres, M.; Salzano, F. M.; Winter, W. P.;
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1004. Serjeant, B.; Myerscough, E.; Serjeant, G. R.; Higgs, D. R.;
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and in vitro. Am. J. Hemat. 14: 315-324, 1983.

1113. Wada, Y.; Ikkala, E.; Imai, K.; Matsuo, T.; Matsuda, H.; Lehtinen,
M.; Hayashi, A.; Lehmann, H.: Structure and function of a new hemoglobin
variant, Hb Meilahti (beta36 (C2) pro-to-thr), characterized by mass
spectrometry. Acta Haemat. 78: 109-113, 1987.

1114. Wade, P. T.; Jenkins, T.; Huehns, E. R.: Haemoglobin variant
in a Bushman: haemoglobin D beta-Bushman (16 gly to arg). Nature 216:
688-690, 1967.

1115. Wajcman, H.; Aguilar i Bascompte, J. L.; Labie, D.; Poyart,
C.; Bohn, B.: Structural and functional studies of hemoglobin Barcelona
(beta94 asp-to-his). J. Molec. Biol. 156: 185-202, 1982.

1116. Wajcman, H.; Amegnizin, K. P. E.; Belkhodja, O.; Labie, D.;
Kernemp, R.: Hemoglobin J (Lome) (beta 59 (E3) lys-to-asn): a new
fast moving variant found in a Togolese. FEBS Lett. 84: 372-374,
1977.

1117. Wajcman, H.; Baudin-Chich, V.; Kister, J.; Feo, C.; Gombaud-Saintonge,
G.; Bohn, B.; Marden, M.; Pagnier, J.; Poyart, C.; Dode, C.; Galacteros,
F.; Blouquit, Y.; Cynober, T.; Tchernia, G.: Hemoglobin J Guantanamo
(beta128 (H6) ala-to-asp) in association with hemoglobin C and alpha-thalassemia
in a family from Benin. Am. J. Hemat. 28: 170-175, 1988.

1118. Wajcman, H.; Blouquit, Y.; Vasseur, C.; Le Querrec, A.; Laniece,
M.; Melevendi, C.; Rasore, A.; Galacteros, F.: Two new human hemoglobin
variants caused by unusual mutational events: Hb Zaire contains a
five residue repetition within the alpha-chain and Hb Duino has two
residues substituted in the beta-chain. Hum. Genet. 89: 676-680,
1992.

1119. Wajcman, H.; Drupt, F.; Henthorn, J. S.; Kister, J.; Prehu,
C.; Riou, J.; Prome, D.; Galacteros, F.: Two new variants with the
same substitution at position beta-122: Hb Bushey (beta-122(GH5)phe-to-leu)
and Hb Casablanca (beta-65(E9)lys-to-met); beta-122(GH5)phe-to-leu). Hemoglobin 24:
125-132, 2000.

1120. Wajcman, H.; Girodon, E.; Prome, D.; North, M. L.; Plassa, F.;
Duwig, I.; Kister, J.; Bergerat, J. P.; Oberling, F.; Lampert, E.;
Lonsdorfer, J.; Goossens, M.; Galacteros, F.: Germline mosaicism
for an alanine to valine substitution at residue beta 140 in hemoglobin
Puttelange, a new variant with oxygen affinity. Hum. Genet. 96:
711-716, 1995.

1121. Wajcman, H.; Kilmartin, J. V.; Najman, A.; Labie, D.: Hemoglobin
Cochin-Port-Royal: consequences of the replacement of the beta chain
C-terminal by an arginine. Biochim. Biophys. Acta 400: 354-364,
1975.

1122. Wajcman, H.; Kister, J.; M'Rad, A.; Prome, D.; Milpied, N.;
Rapp, M. J.; Harousseau, J. L.; Riou, J.; Bardakdjian, J.; Galacteros,
F.: Hb Saint Nazaire (beta-103[G5]phe-to-ile): a new example of polycythemia
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Hemat. 44: 16-21, 1993.

1123. Wajcman, H.; Kister, J.; Marden, M.; Bohn, B.; Blouquit, Y.;
Descamps, J.; Goudemand, M.; Poyart, C.; Galacteros, F.: Hemoglobin
Calais (beta76 (E20) ala-to-pro): a hemoglobin variant with decreased
intrinsic oxygen affinity. Biochim. Biophys. Acta 1096: 60-66, 1991.

1124. Wajcman, H.; Kister, J.; Prehu, C.; Riou, J.; Godart, C.; Bardakdjian,
J.; Soummer, A. M.; Prome, D.; Galacteros, F.: Hb Tende [beta-124(H2)pro
to leu]: a new variant with a moderate increase in oxygen affinity. Hemoglobin 22:
517-523, 1998.

1125. Wajcman, H.; Kister, J.; Prome, D.; Galacteros, F.; Gilsanz,
F.: Hb Villaverde [beta-89 (F5) ser-to-thr]: the structural modification
of an intrasubunit contact is responsible for a high oxygen affinity. Biochim.
Biophys. Acta 1225: 89-94, 1993.

1126. Wajcman, H.; Kister, J.; Vasseur, C.; Blouquit, Y.; Trastour,
J. C.; Cottenceau, D.; Galacteros, F.: Structure of the EF corner
favors deamidation of asparaginyl residues in hemoglobin: the example
of Hb La Roche-sur-Yon [beta 81(EF5)leu to his]. Biochim. Biophys.
Acta 1138: 127-132, 1992.

1127. Wajcman, H.; Krishnamoorthy, R.; Gacon, G.; Elion, J.; Allard,
C.; Labie, D.: A new hemoglobin variant involving the distal histidine:
Hb Bicetre (beta 63(E7) his-to-pro). J. Molec. Med. 1: 187-197,
1976.

1128. Wajcman, H.; Labie, D.; Schapira, G.: Hemoglobin Tours: thr
beta-87 (F3) deleted and hemoglobin St. Antoine: gly-to-leu beta-74-75
(E18-19) deleted: consequences for oxygen affinity and protein stability. Biochim.
Biophys. Acta 295: 495-504, 1973.

1129. Wajcman, H.; Lahary, A.; Prome, D.; Kister, J.; Riou, J.; Godart,
C.; Prehu, C.; Traeger-Synodinos, J.; Papassotiriou, I.; Galacteros,
F.: Hb Mont Saint Aignan (beta-128(H6)ala-to-pro): a new unstable
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1130. Wajcman, H.; Mrad, A.; Blouquit, Y.; Parmentier, C.; Riou, J.;
Galacteros, F.: Hemoglobin Villejuif (beta123(H1)thr-to-ile): a new
variant found in coincidence with polycythemia vera. Am. J. Hemat. 32:
294-297, 1989.

1131. Wajcman, H.; Riou, J.; Prome, D.; Kister, J.; Galacteros, F.
: Hb Brie Comte Robert (beta-36(C2)pro-to-ala): a new hemoglobin variant
with high oxygen affinity and marked hydrophobic properties. Hemoglobin 23:
281-286, 1999.

1132. Wajcman, H.; Vasseur, C.; Blouquit, Y.; Santo, D. E.; Peres,
M. J.; Martins, M. C.; Poyart, C.; Galacteros, F.: Hemoglobin Redondo
[beta 92(F8) his-to-asn]: an unstable hemoglobin variant associated
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1991.

1133. Walker, L.; McFarlane, A.; Patterson, M.; Eng, B.; Waye, J.
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1134. Watson-Williams, E. J.; Beale, D.; Irvine, D.; Lehmann, H.:
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1135. Waye, J. S.; Eng, B.; Patterson, M.; Chui, D. H. K.; Fernandes,
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1136. Waye, J. S.; Eng, B.; Patterson, M.; Chui, D. H. K.; Fernandes,
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1137. Waye, J. S.; Walker, L.; Lafferty, J.; Lemire, E. G.; Chui,
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1138. Weatherall, D.; Clegg, J.: The Thalassemia Syndromes. 4th ed. Oxford:
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1139. Weatherall, D. J.: The inherited diseases of hemoglobin are
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1141. Weatherall, D. J.; Clegg, J. B.: The Thalassaemia Syndromes.
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1142. Weatherall, D. J.; Clegg, J. B.; Collender, S. T.; Wells, R.
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1143. Weatherall, D. J.; Clegg, J. B.; Knox-Macaulay, H. H. M.; Bunch,
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1144. Weaver, G. A.; Rahbar, S.; Ellsworth, C. A.; de Alarcon, P.
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1145. Weinstein, B. I.; White, J. M.; Wiltshire, A.; Lehmann, H.:
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1146. Welch, S. G.: Haemoglobin G-Szuhu beta 80 asn-to-lys in an
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1147. Welch, S. G.; Bateman, C.: Hb D-Neath or beta121 (GH4) glu-to-ala:
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1148. Went, L. N.; MacIver, J. E.: Sickle-cell haemoglobin-J disease. Brit.
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1149. Westaway, D.; Williamson, R.: An intron nucleotide sequence
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1150. White, J. M.; Brain, M. C.; Lorkin, P. A.; Lehmann, H.; Smith,
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1151. White, J. M.; Szur, L.; Gillies, I. D. S.; Lorkin, P. A.; Lehmann,
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1152. Wiedermann, B. F.; Indrak, K.; Wilson, J. B.; Webber, B. B.;
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1153. Wilkinson, T.; Brennan, S. O.; Carrell, R. W.; Wells, R. M.;
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1154. Wilkinson, T.; Chua, C. G.; Carrell, R. W.; Robin, H.; Exner,
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1155. Wilkinson, T.; Como, P.; Brock, P.; Kronenberg, H.; Trent, R.
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1156. Wilkinson, T.; Kronenberg, H.; Isaacs, W. A.; Lehmann, H.:
Haemoglobin J Baltimore interacting with beta-thalassaemia in an Australian
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1157. Williamson, D.; Beresford, C. H.; Langdown, J. V.; Anderson,
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1158. Williamson, D.; Brennan, S. O.; Carrell, R. W.: Hb Brisbane
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1159. Williamson, D.; Brennan, S. O.; Muir, H.; Carrell, R. W.: Hemoglobin
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1160. Williamson, D.; Nutkins, J.; Rosthoj, S.; Brennan, S. O.; Williams,
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1161. Williamson, D.; Perry, D. J.; Brown, K.; Langdown, J. V.; de
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27-32, 1995.

1162. Williamson, D.; Wells, R. M. G.; Anderson, R.; Matthews, J.
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1163. Williamson, R.; Eskdale, J.; Coleman, D. V.; Niazi, M.; Loeffler,
F. E.; Modell, B. M.: Direct gene analysis of chorionic villi: a
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1125-1127, 1981. Note: Originally Volume II.

1164. Wilson, C. I. D.; Cave, R. J.; Lehmann, H.; Close, M.; Imai,
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1165. Wilson, G.; Forrest, P.; Heppinstall, S.; Green, B. N.; Goodeve,
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G-San Jose beta 7 (A4) glu-to-gly in a Mexican family. Hemoglobin 4:
95-99, 1980.

1167. Wilson, J. B.; Ramachandran, M.; Webber, B. B.; Kutlar, F.;
Hazelwood, L. F.; Barnett, D.; Hirschler, N. V.; Huisman, T. H. J.
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269-278, 1991.

1168. Wilson, J. B.; Webber, B. B.; Hu, H.; Kutlar, A.; Kutlar, F.;
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1169. Wilson, J. T.; Forget, B. G.; Wilson, L. B.; Weissman, S. M.
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1170. Wilson, J. T.; Milner, P. F.; Summer, M. E.; Nallaseth, F. S.;
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Use of restriction endonucleases for mapping the allele for beta-S-globin. Proc.
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1171. Winslow, R. M.; Charache, S.: Hemoglobin Richmond: subunit
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1172. Winslow, R. M.; Swenberg, M.-L.; Gross, E.; Chervenick, P.;
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1173. Witkowska, H. E.; Lubin, B. H.; Beuzard, Y.; Baruchel, S.; Esseltine,
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1174. Witkowski, J. A.: The 51 most-cited articles in the Cold Spring
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1175. Wong, C.; Antonarakis, S. E.; Goff, S. C.; Orkin, S. H.; Boehm,
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1176. Wong, C.; Antonarakis, S. E.; Goff, S. C.; Orkin, S. H.; Forget,
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1177. Wong, C.; Dowling, C. E.; Saiki, R. K.; Higuchi, R. G.; Erlich,
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1178. Wong, S. C.; Ali, M. A. M.; Lam, H.; Webber, B. B.; Wilson,
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1179. Wong, S. C.; Ali, M. A. M.; Nicholson, W.; Wilson, J. B.; Lam,
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1180. Wong, S. C.; Bouver, N.; Wilson, J. B.; Huisman, T. H. J.:
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521-522, 1971.

1181. Wood, E. T.; Stover, D. A.; Slatkin, M.; Nachman, M. W.; Hammer,
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1182. Woodson, R. D.; Heywood, J. D.; Lenfant, C.: Oxygen transport
in hemoglobin San Francisco. Clin. Res. 18: 134, 1970.

1183. Worthington, S.; Lehmann, H.: The first observation of Hb D
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1184. Yamada, H.; Hotta, H.; Ohba, Y.; Miyaji, T.; Ito, J.; Minami,
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245-256, 1977.

1185. Yamagishi, Y.; Ikeda, K.; Takahara, J.; Irino, S.; Hasui, H.;
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1186. Yamashiro, Y.; Hattori, Y.; Matsuno, Y.; Ohba, Y.; Miyaji, T.;
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1187. Yanase, T.; Hanada, M.; Seita, M.; Ohya, I.; Ohta, Y.; Imamura,
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1188. Yang, K. G.; Kutlar, F.; George, E.; Wilson, J. B.; Kutlar,
A.; Stoming, T. A.; Gonzalez-Redondo, J. M.; Huisman, T. H. J.: Molecular
characterization of beta-globin gene mutations in Malay patients with
Hb E-beta-thalassaemia and thalassaemia major. Brit. J. Haemat. 72:
73-80, 1989.

1189. Yapo, A. P.; Prome, D.; Claparols, C.; Riou, J.; Galacteros,
F.; Wajcman, H.: Hb Yaounde (beta-134(H12)val-to-ala), a new neutral
variant found in association with Hb Kenitra (beta-69(E13)gly-to-arg)
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1190. Yeager, A. M.; Zinkham, W. H.; Jue, D. L.; Winslow, R. M.; Johnson,
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unstable hemoglobin associated with chronic mild anemia. Pediat.
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1191. Yoon, K.; Cole-Strauss, A.; Kmiec, E. B.: Targeted gene correction
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1192. Zak, S. J.; Brimhall, B.; Jones, R. T.; Kaplan, M. E.: Hemoglobin
Andrew-Minneapolis (beta 144 lys-to-asn): a new high-oxygen affinity
mutant human hemoglobin. Blood 44: 543-549, 1974.

1193. Zeng, F.; Rodgers, G. P.; Huang, S.; Schechter, A. N.; Salamah,
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1194. Zeng, Y.; Huang, S.: Hemoglobin New York (beta 113(G15) val-to-glu)
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1195. Zeng, Y.; Huang, S.; Ren, Z.; Li, H.: Identification of Hb
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1196. Zeng, Y.; Huang, S.; Tao, Y.; Wang, B.; Gu, Y.; Chen, R.: Hemoglobin
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1197. Zeng, Y. T.; Ren, Z. R.; Chen, M. J.; Zhao, J. Q.; Qiu, X. K.;
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1198. Zhao, W.; Wilson, J. B.; Huisman, T. H. J.; Sciarratta, G. V.;
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1199. Zhao, W.; Wilson, J. B.; Webber, B. B.; Huisman, T. H. J.; Sciarratta,
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1200. Zhu, L. H.; Li, M.; Wang, S. J.: Hemoglobin J-Guantanamo (beta128
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1203. Zinkham, W. H.; Houtchens, R. A.; Caughey, W. S.: Relation
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1205. Zinkham, W. H.; Vangrov, J. S.; Dixon, S. M.; Hutchison, J.
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*FIELD* CS
Heme:
Beta polypeptide hemoglobin chain;
Anemia;
Microcytosis;
Hypochromia;
Congenital dyserythropoietic anemia (Irish type);
Mild hemolytic anemia (e.g. Hb Extremadura 141900.0074);
Hemolytic microcytic anemia in compound heterozygosity with Hb C (e.g.
Hb Korle-bu 141900.0153);
Macrocytic hemolytic disease (e.g. Hb Redondo 141900.0404);
Erythrocytosis (e.g. Hb Brigham 141900.0028);
Congenital Heinz body anemia (e.g. Hb Bruxelles 141900.0033);
Sickle cell anemia (homozygous Hb SS 141900.0243);
Painful crises;
Aplastic crises;
Acute splenic sequestration;
Splenomegaly;
Dactylitis;
Ischemia;
Avascular necrosis;
Leg ulcers;
Cholelithiasis;
Priapism;
Osteonecrosis;
Osteomyelitis;
Drug-induced hemolysis (e.g. Hb Zurich 141900.0310) Methemoglobinemia
(e.g., HbM Saskatoon 141900.0165) Erythremia (e.g., Hb Osler 141900.0211)

Skin:
Jaundice;
Cyanosis (e.g. Hb M Saskatoon 141900.0165)

GI:
Cholelithiasis;
Splenomegaly (e.g. Hb Jacksonville 141900.0401);
Splenic syndrome (e.g. Hb S 141900.0243)

GU:
Hematuria (e.g. Hb Sarrebourg 141900.0435);
Urine concentrating defect (e.g. Hb S 141900.0243)

Misc:
Resistance to falciparum malaria (e.g. Hb S. 141900.0243);
Beta-delta fusion variant (e.g. Hb Lincoln Park 141900.0157);

Lab:
Abnormal red cell morphology;
Bone marrow erythroid hyperplasia;
Increased numbers of multinucleate red cell precursors;
Inclusion bodies in normoblasts;
Altered hemoglobin A(2) levels;
Altered hemoglobin F levels;
Unstable hemoglobin (e.g. Hb Koln 141900.0151);
Diminished oxygen affinity (e.g. Hb Chico 141900.0048);
Increased oxygen affinity (e.g. Hb Heathrow 141900.0102);
Increased N-terminal glycation (e.g. Hb Himeji 141900.0107);
Discrepant Hb A1c measurement (e.g. Hb Marseille 141900.0171);
Unusually low Hb A(1c) level (e.g. Hb Kodaira 141900.0409);
Red cell inclusion bodies (e.g. Hb Matera 141900.0173);
Red cell sickling (e.g. Hb S 141900.0243);
Non-Hb S red cell sickling (e.g. Hb C (Georgetown) 141900.0039);
Electrophoretic migration as Hb S (e.g. Hb Muskegon 141900.0432);
Increased red cell sickling tendency (e.g. Hb S (OMAN) 141900.0245)

Inheritance:
Autosomal dominant for some such as methemoglobinemia, polycythemia,
and Heinz body hemolytic anemia;
Autosomal recessive for others such as sickle cell disease and thalassemia
major

*FIELD* CN
Victor A. McKusick - updated: 11/25/1998

*FIELD* ED
joanna: 11/25/1998

*FIELD* CN
Cassandra L. Kniffin - updated: 2/14/2013
Cassandra L. Kniffin - updated: 1/22/2013
Ada Hamosh - updated: 11/1/2012
Paul J. Converse - updated: 2/13/2012
jjjjjjjjjjjjjjkkk jjj kkjjqq: 1/12/2012
Ada Hamosh - updated: 1/4/2012
Paul J. Converse - updated: 11/17/2011
Carol A. Bocchini - updated: 5/20/2011
Ada Hamosh - updated: 9/29/2010
Paul J. Converse - updated: 5/14/2010
Patricia A. Hartz - updated: 1/28/2010
Paul J. Converse - updated: 11/11/2009
Carol A. Bocchini - updated: 5/22/2009
Paul J. Converse - updated: 3/13/2008
Cassandra L. Kniffin - updated: 2/20/2008
George E. Tiller - updated: 1/3/2008
Matthew B. Gross - updated: 7/5/2007
Victor A. McKusick - updated: 2/26/2007
Victor A. McKusick - updated: 11/21/2006
Victor A. McKusick - updated: 10/19/2006
Victor A. McKusick - updated: 9/19/2006
Victor A. McKusick - updated: 3/29/2006
George E. Tiller - updated: 2/17/2006
Victor A. McKusick - updated: 1/30/2006
George E. Tiller - updated: 1/23/2006
Victor A. McKusick - updated: 10/10/2005
Victor A. McKusick - updated: 10/3/2005
Victor A. McKusick - updated: 8/11/2005
Ada Hamosh - updated: 7/27/2005
Victor A. McKusick - updated: 6/20/2005
Victor A. McKusick - updated: 5/11/2005
Victor A. McKusick - updated: 3/7/2005
Victor A. McKusick - updated: 3/3/2005
Ada Hamosh - updated: 2/1/2005
Victor A. McKusick - updated: 12/9/2004
Victor A. McKusick - updated: 12/6/2004
Victor A. McKusick - updated: 10/26/2004
John A. Phillips, III - updated: 9/24/2004
Victor A. McKusick - updated: 9/21/2004
Victor A. McKusick - updated: 8/6/2004
Victor A. McKusick - updated: 6/2/2004
Victor A. McKusick - updated: 2/2/2004
Victor A. McKusick - updated: 1/20/2004
Victor A. McKusick - updated: 1/15/2004
Victor A. McKusick - updated: 4/17/2003
Victor A. McKusick - updated: 3/4/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 11/19/2002
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 9/27/2002
Victor A. McKusick - updated: 9/16/2002
Victor A. McKusick - updated: 8/15/2002
Victor A. McKusick - updated: 6/3/2002
Victor A. McKusick - updated: 5/31/2002
Victor A. McKusick - updated: 5/23/2002
Victor A. McKusick - updated: 4/18/2002
Victor A. McKusick - updated: 4/16/2002
Victor A. McKusick - updated: 4/4/2002
Victor A. McKusick - updated: 2/27/2002
Victor A. McKusick - updated: 1/22/2002
Ada Hamosh - updated: 11/15/2001
Victor A. McKusick - updated: 11/2/2001
Victor A. McKusick - updated: 11/1/2001
Victor A. McKusick - updated: 10/10/2001
Victor A. McKusick - updated: 2/28/2001
Victor A. McKusick - updated: 2/14/2001
Victor A. McKusick - updated: 11/3/2000
Ada Hamosh - updated: 10/19/2000
Victor A. McKusick - updated: 8/31/2000
Victor A. McKusick - updated: 8/16/2000
Victor A. McKusick - updated: 7/21/2000
George E. Tiller - updated: 5/2/2000
Victor A. McKusick - updated: 4/26/2000
Victor A. McKusick - updated: 4/11/2000
Victor A. McKusick - updated: 1/21/2000
Victor A. McKusick - updated: 1/18/2000
Carol A. Bocchini - updated: 12/14/1999
Victor A. McKusick - updated: 12/8/1999
Victor A. McKusick - updated: 9/15/1999
Matthew B. Gross - updated: 8/26/1999
Victor A. McKusick - updated: 8/25/1999
Victor A. McKusick - updated: 8/13/1999
Wilson H. Y. Lo - updated: 8/12/1999
Victor A. McKusick - updated: 7/20/1999
Ada Hamosh - updated: 6/27/1999
Victor A. McKusick - updated: 5/24/1999
Victor A. McKusick - updated: 12/21/1998
Stylianos E. Antonarakis - updated: 12/13/1998
Victor A. McKusick - updated: 11/19/1998
Victor A. McKusick - updated: 8/26/1998
Victor A. McKusick - edited: 8/19/1998
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 3/31/1998
Victor A. McKusick - updated: 2/17/1998
Victor A. McKusick - updated: 11/5/1997
Victor A. McKusick - updated: 9/29/1997
Victor A. McKusick - updated: 9/11/1997
Victor A. McKusick - updated: 8/13/1997
Victor A. McKusick - updated: 5/28/1997
Victor A. McKusick - updated: 2/28/1997
Victor A. McKusick - edited: 2/21/1997
Iosif W. Lurie - updated: 1/17/1997
Moyra Smith - updated: 9/5/1996
Moyra Smith - updated: 8/15/1996
Orest Hurko - updated: 6/13/1995

*FIELD* CD
Victor A. McKusick: 6/24/1986

*FIELD* ED
terry: 03/14/2013
alopez: 2/20/2013
ckniffin: 2/14/2013
carol: 2/6/2013
ckniffin: 1/22/2013
carol: 12/12/2012
alopez: 11/2/2012
terry: 11/1/2012
alopez: 9/21/2012
terry: 7/6/2012
carol: 2/27/2012
mgross: 2/16/2012
terry: 2/13/2012
alopez: 1/12/2012
terry: 1/4/2012
joanna: 12/20/2011
mgross: 11/17/2011
carol: 6/13/2011
carol: 5/23/2011
carol: 5/20/2011
terry: 5/20/2011
carol: 5/20/2011
carol: 5/18/2011
terry: 11/3/2010
terry: 10/12/2010
alopez: 10/5/2010
terry: 9/29/2010
carol: 8/5/2010
mgross: 5/17/2010
terry: 5/14/2010
wwang: 3/26/2010
alopez: 1/28/2010
carol: 1/8/2010
terry: 12/16/2009
mgross: 12/1/2009
terry: 11/11/2009
wwang: 7/29/2009
carol: 6/3/2009
carol: 5/22/2009
terry: 2/4/2009
terry: 1/14/2009
mgross: 3/19/2008
terry: 3/13/2008
wwang: 3/6/2008
ckniffin: 2/20/2008
wwang: 1/11/2008
terry: 1/3/2008
terry: 8/9/2007
mgross: 7/5/2007
alopez: 3/21/2007
terry: 2/26/2007
alopez: 11/27/2006
terry: 11/21/2006
alopez: 10/23/2006
terry: 10/19/2006
wwang: 10/3/2006
terry: 9/19/2006
terry: 6/23/2006
alopez: 5/5/2006
terry: 3/29/2006
wwang: 3/2/2006
terry: 2/17/2006
alopez: 2/7/2006
terry: 1/30/2006
carol: 1/24/2006
wwang: 1/23/2006
carol: 1/19/2006
alopez: 10/10/2005
alopez: 10/7/2005
terry: 10/3/2005
carol: 10/3/2005
terry: 9/27/2005
wwang: 8/18/2005
terry: 8/11/2005
terry: 8/3/2005
alopez: 7/28/2005
terry: 7/27/2005
carol: 7/19/2005
alopez: 6/22/2005
terry: 6/20/2005
wwang: 6/7/2005
wwang: 5/12/2005
terry: 5/11/2005
tkritzer: 3/11/2005
terry: 3/7/2005
terry: 3/4/2005
terry: 3/3/2005
tkritzer: 2/1/2005
tkritzer: 1/25/2005
terry: 12/9/2004
terry: 12/6/2004
terry: 11/3/2004
tkritzer: 10/28/2004
terry: 10/26/2004
alopez: 9/24/2004
tkritzer: 9/23/2004
terry: 9/21/2004
tkritzer: 8/10/2004
terry: 8/6/2004
tkritzer: 6/8/2004
terry: 6/2/2004
alopez: 5/27/2004
terry: 5/20/2004
tkritzer: 4/7/2004
terry: 4/2/2004
carol: 3/17/2004
tkritzer: 2/2/2004
terry: 2/2/2004
tkritzer: 1/22/2004
terry: 1/20/2004
terry: 1/15/2004
carol: 11/24/2003
alopez: 11/14/2003
alopez: 11/10/2003
cwells: 11/7/2003
carol: 8/25/2003
terry: 7/30/2003
carol: 5/13/2003
tkritzer: 4/30/2003
terry: 4/17/2003
carol: 3/11/2003
tkritzer: 3/7/2003
terry: 3/4/2003
terry: 3/3/2003
tkritzer: 12/31/2002
tkritzer: 11/27/2002
tkritzer: 11/20/2002
terry: 11/19/2002
tkritzer: 10/7/2002
tkritzer: 10/3/2002
tkritzer: 10/2/2002
carol: 9/27/2002
carol: 9/16/2002
tkritzer: 8/20/2002
tkritzer: 8/16/2002
terry: 8/15/2002
carol: 7/29/2002
alopez: 6/18/2002
terry: 6/3/2002
terry: 5/31/2002
alopez: 5/28/2002
terry: 5/23/2002
cwells: 5/1/2002
cwells: 4/24/2002
terry: 4/18/2002
terry: 4/16/2002
cwells: 4/15/2002
cwells: 4/10/2002
terry: 4/4/2002
cwells: 3/22/2002
cwells: 3/20/2002
terry: 2/27/2002
terry: 2/8/2002
carol: 2/5/2002
mcapotos: 1/31/2002
terry: 1/22/2002
alopez: 11/15/2001
terry: 11/15/2001
carol: 11/8/2001
mcapotos: 11/2/2001
mcapotos: 11/1/2001
carol: 10/12/2001
terry: 10/10/2001
terry: 2/28/2001
carol: 2/26/2001
terry: 2/26/2001
carol: 2/20/2001
mcapotos: 2/19/2001
mcapotos: 2/16/2001
terry: 2/14/2001
mcapotos: 2/12/2001
mcapotos: 1/12/2001
mcapotos: 11/9/2000
terry: 11/3/2000
alopez: 10/19/2000
terry: 9/15/2000
terry: 8/31/2000
carol: 8/29/2000
terry: 8/16/2000
alopez: 7/26/2000
terry: 7/21/2000
carol: 6/22/2000
alopez: 5/2/2000
mcapotos: 5/2/2000
mcapotos: 4/28/2000
mcapotos: 4/27/2000
terry: 4/26/2000
terry: 4/11/2000
terry: 1/21/2000
mcapotos: 1/20/2000
mgross: 1/19/2000
terry: 1/18/2000
mcapotos: 12/15/1999
carol: 12/14/1999
carol: 12/9/1999
terry: 12/8/1999
carol: 10/5/1999
mgross: 9/22/1999
mgross: 9/21/1999
terry: 9/15/1999
carol: 9/8/1999
carol: 8/26/1999
mgross: 8/26/1999
mgross: 8/25/1999
mgross: 8/13/1999
mgross: 8/12/1999
jlewis: 8/5/1999
terry: 7/20/1999
kayiaros: 7/13/1999
carol: 6/27/1999
carol: 5/24/1999
joanna: 5/20/1999
carol: 12/29/1998
terry: 12/21/1998
carol: 12/13/1998
carol: 11/25/1998
terry: 11/19/1998
joanna: 11/19/1998
carol: 8/27/1998
terry: 8/26/1998
terry: 8/19/1998
dkim: 7/24/1998
dkim: 7/21/1998
carol: 6/26/1998
terry: 6/18/1998
alopez: 6/9/1998
dholmes: 6/8/1998
alopez: 5/14/1998
carol: 5/12/1998
terry: 4/30/1998
alopez: 3/31/1998
terry: 3/24/1998
mark: 3/2/1998
terry: 2/17/1998
jenny: 11/7/1997
terry: 11/5/1997
mark: 10/28/1997
mark: 10/10/1997
jenny: 10/1/1997
terry: 9/29/1997
terry: 9/26/1997
dholmes: 9/26/1997
dholmes: 9/19/1997
jenny: 9/18/1997
terry: 9/11/1997
terry: 9/8/1997
terry: 8/13/1997
joanna: 8/12/1997
terry: 8/6/1997
alopez: 7/31/1997
alopez: 7/28/1997
terry: 7/10/1997
alopez: 7/10/1997
mark: 7/10/1997
alopez: 7/10/1997
mark: 7/8/1997
terry: 7/7/1997
jenny: 6/3/1997
terry: 5/28/1997
mark: 2/28/1997
terry: 2/26/1997
mark: 2/21/1997
jamie: 1/17/1997
jamie: 1/15/1997
terry: 1/7/1997
mark: 12/23/1996
terry: 12/18/1996
terry: 12/17/1996
terry: 12/5/1996
terry: 11/18/1996
terry: 11/15/1996
terry: 11/13/1996
terry: 11/5/1996
terry: 10/31/1996
jamie: 10/30/1996
mark: 9/11/1996
mark: 9/5/1996
terry: 9/5/1996
marlene: 9/3/1996
mark: 8/15/1996
mark: 7/9/1996
mark: 7/2/1996
terry: 6/25/1996
mark: 6/19/1996
terry: 6/12/1996
terry: 6/5/1996
mark: 4/22/1996
terry: 4/15/1996
mark: 3/30/1996
mark: 3/21/1996
terry: 3/21/1996
mark: 3/11/1996
terry: 2/28/1996
mark: 2/13/1996
terry: 2/5/1996
mark: 1/28/1996
terry: 1/23/1996
mark: 1/10/1996
mark: 1/4/1996
mark: 11/13/1995
terry: 10/31/1995
davew: 8/25/1994
jason: 7/29/1994
pfoster: 4/5/1994