RBCC

Full text data of HBA1

HBA1 [Confidence: high (present in two of the MS resources)]
Hemoglobin subunit alpha (Alpha-globin; Hemoglobin alpha chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00410714
IPI00410714 Hemoglobin alpha chain Involved in oxygen transport from the lung to the various peripheral tissues soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight

UniProt P69905
ID HBA_HUMAN Reviewed; 142 AA.
AC P69905; P01922; Q1HDT5; Q3MIF5; Q53F97; Q96KF1; Q9NYR7; Q9UCM0;
read moreDT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Hemoglobin subunit alpha;
DE AltName: Full=Alpha-globin;
DE AltName: Full=Hemoglobin alpha chain;
GN Name=HBA1;
GN and
GN Name=HBA2;
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] (HBA1).
RX PubMed=7448866; DOI=10.1016/0092-8674(80)90347-5;
RA Michelson A.M., Orkin S.H.;
RT "The 3' untranslated regions of the duplicated human alpha-globin
RT genes are unexpectedly divergent.";
RL Cell 22:371-377(1980).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (HBA2).
RX PubMed=6244294;
RA Wilson J.T., Wilson L.B., Reddy V.B., Cavallesco C., Ghosh P.K.,
RA Deriel J.K., Forget B.G., Weissman S.M.;
RT "Nucleotide sequence of the coding portion of human alpha globin
RT messenger RNA.";
RL J. Biol. Chem. 255:2807-2815(1980).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (HBA2).
RX PubMed=6452630; DOI=10.1073/pnas.77.12.7054;
RA Liebhaber S.A., Goossens M.J., Kan Y.W.;
RT "Cloning and complete nucleotide sequence of human 5'-alpha-globin
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:7054-7058(1980).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6946451; DOI=10.1073/pnas.78.8.5041;
RA Orkin S.H., Goff S.C., Hechtman R.L.;
RT "Mutation in an intervening sequence splice junction in man.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:5041-5045(1981).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-32.
RX PubMed=11410421;
RA Zhao Y., Xu X.;
RT "Alpha2(CD31 AGG-->AAG, Arg-->Lys) causing non-deletional alpha-
RT thalassemia in a Chinese family with HbH disease.";
RL Haematologica 86:541-542(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (HBA1).
RX PubMed=11402454;
RA Zhao Y., Zhong M., Liu Z., Xu X.;
RT "Rapid detection of the common alpha-thalassemia-2 determinants by PCR
RT assay.";
RL Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18:216-218(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALPHA-1 AND ALPHA-2).
RX PubMed=16728641; DOI=10.1126/science.1126431;
RA De Gobbi M., Viprakasit V., Hughes J.R., Fisher C., Buckle V.J.,
RA Ayyub H., Gibbons R.J., Vernimmen D., Yoshinaga Y., de Jong P.,
RA Cheng J.-F., Rubin E.M., Wood W.G., Bowden D., Higgs D.R.;
RT "A regulatory SNP causes a human genetic disease by creating a new
RT transcriptional promoter.";
RL Science 312:1215-1217(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (HBA2).
RC TISSUE=Blood;
RA Kutlar F., Leithner C., Kutlar A.;
RT "Rapid sequencing of mRNA of the human alpha two globin, directly
RT isolated from reticulocytes in whole blood.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (HBA1).
RC TISSUE=Blood;
RA Kutlar F., Leithner C., Kutlar A.;
RT "cDNA sequencing of human alpha one globin mRNA, the 3'untranslated
RT region is different than alpha two globin.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Blood;
RA Kutlar F., Holley L., Leithner C., Kutlar A.;
RT "An alpha chain variant 'Hemoglobin J-Toronto (Cd.5 /Ala to Asp)'
RT mutation was detected on the alpha-1 globin mRNA by sequencing of
RT cDNA.";
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (HBA2), AND VARIANT EVANS MET-63.
RC TISSUE=Blood;
RA Kutlar F., Elam D., Hoff J.V., Holley L., Kutlar A.;
RT "Unstable Hb 'Evans' (GTG->ATG/Val 62 Met) was detected on the alpha-2
RT globin gene of an Hispanic girl.";
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (HBA2), AND VARIANT G-PHILADELPHIA
RP LYS-69.
RA Kutlar F., Davis D.H., Nechtman J., Elam D.;
RT "Hb G-Philadelphia (Alpha,Codon 68;AAC>AAG/Asn>Lys)in black is
RT detected on a chromosome that carries alpha 3.7 kb deletion showed
RT completely normal alpha-2 globin gene sequence.";
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thymus;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (HBA1 AND HBA2).
RX PubMed=11157797; DOI=10.1093/hmg/10.4.339;
RA Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K.,
RA Tufarelli C., Kearney L., Buckle V.J., Doggett N.A., Flint J.,
RA Higgs D.R.;
RT "Sequence, structure and pathology of the fully annotated terminal 2
RT Mb of the short arm of human chromosome 16.";
RL Hum. Mol. Genet. 10:339-352(2001).
RN [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (HBA1 AND HBA2).
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [16]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (HBA1 AND HBA2).
RC TISSUE=Bone marrow, Brain, Lung, and Spleen;
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 [17]
RP PROTEIN SEQUENCE OF 2-142.
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 [18]
RP PROTEIN SEQUENCE OF 2-142.
RX PubMed=13954546;
RA Hill R.J., Konigsberg W.;
RT "The structure of human hemoglobin: IV. The chymotryptic digestion of
RT the alpha chain of human hemoglobin.";
RL J. Biol. Chem. 237:3151-3156(1962).
RN [19]
RP PROTEIN SEQUENCE OF 2-142.
RX PubMed=14093912; DOI=10.1021/bi00906a030;
RA Schroeder W.A., Shelton J.R., Shelton J.B., Cormick J.;
RT "The amino acid sequence of the alpha chain of human fetal
RT hemoglobin.";
RL Biochemistry 2:1353-1357(1963).
RN [20]
RP PROTEIN SEQUENCE OF 2-32.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [21]
RP PROTEIN SEQUENCE OF 128-142, AND VARIANT ETHIOPIA HIS-141.
RC TISSUE=Umbilical cord blood;
RX PubMed=1428951;
RA Webber B.B., Wilson J.B., Gu L.-H., Huisman T.H.J.;
RT "Hb Ethiopia or alpha 2(140)(HC2)Tyr----His beta 2.";
RL Hemoglobin 16:441-443(1992).
RN [22]
RP GLYCATION AT LYS-8; LYS-17; LYS-41 AND LYS-62, AND LACK OF GLYCATION
RP AT LYS-12; LYS-57; LYS-61; LYS-91 AND LYS-100.
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 [23]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-17, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [24]
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 [25]
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 [26]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
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 [27]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF LIGANDED R2 STATE.
RX PubMed=1512262;
RA Silva M.M., Rogers P.H., Arnone A.;
RT "A third quaternary structure of human hemoglobin A at 1.7-A
RT resolution.";
RL J. Biol. Chem. 267:17248-17256(1992).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF HB GOWER-2.
RX PubMed=9665850; DOI=10.1006/jmbi.1998.1868;
RA Sutherland-Smith A.J., Baker H.M., Hofmann O.M., Brittain T.,
RA Baker E.N.;
RT "Crystal structure of a human embryonic haemoglobin: the carbonmonoxy
RT form of Gower II (alpha2 epsilon2) haemoglobin at 2.9-A resolution.";
RL J. Mol. Biol. 280:475-484(1998).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF VARIANT HB CATONSVILLE GLU-38
RP INS.
RX PubMed=8448109; DOI=10.1021/bi00061a007;
RA Kavanaugh J.S., Moo-Penn W.F., Arnone A.;
RT "Accommodation of insertions in helices: the mutation in hemoglobin
RT Catonsville (Pro 37 alpha-Glu-Thr 38 alpha) generates a 3(10)-->alpha
RT bulge.";
RL Biochemistry 32:2509-2513(1993).
RN [30]
RP VARIANT AL-AIN ABU DHABI ASP-19.
RX PubMed=1428941;
RA Abbes S., M'Rad A., Fitzgerald P.A., Dormer P., Blouquit Y.,
RA Kister J., Galacteros F., Wajcman H.;
RT "HB Al-Ain Abu Dhabi [alpha 18(A16)Gly-->Asp]: a new hemoglobin
RT variant discovered in an Emiratee family.";
RL Hemoglobin 16:355-362(1992).
RN [31]
RP VARIANT ATAGO TYR-86.
RX PubMed=5115619;
RA Fujiwara N., Maekawa T., Matsuda G.;
RT "Hemoglobin Atago (alpha2-85 Tyr beta-2) a new abnormal human
RT hemoglobin found in Nagasaki. Biochemical studies on hemoglobins and
RT myoglobins. VI.";
RL Int. J. Protein Res. 3:35-39(1971).
RN [32]
RP VARIANT AUCKLAND ASN-88.
RX PubMed=9322075;
RA Brennan S.O., Matthews J.R.;
RT "Hb Auckland [alpha 87(F8) His-->Asn]: a new mutation of the proximal
RT histidine identified by electrospray mass spectrometry.";
RL Hemoglobin 21:393-403(1997).
RN [33]
RP VARIANTS J-BUDA ASN-62 AND G-PEST ASN-75.
RA Brimhall B.J., Duerst M., Hollan S.R., Stenzel P., Szelenyi J.,
RA Jones R.T.;
RT "Structural characterizations of hemoglobins J-Buda (alpha 61 (E10)
RT Lys-to-Asn) and G-Pest (alpha 74 (EF3) Asp-to-Asn).";
RL Biochim. Biophys. Acta 336:344-360(1974).
RN [34]
RP VARIANT CEMENELUM TRP-93.
RX PubMed=8148419; DOI=10.1007/BF01715134;
RA Wajcman H., Kister J., M'Rad A., Soummer A.M., Galacteros F.;
RT "Hb Cemenelum [alpha 92 (FG4) Arg-->Trp]: a hemoglobin variant of the
RT alpha 1/beta 2 interface that displays a moderate increase in oxygen
RT affinity.";
RL Ann. Hematol. 68:73-76(1994).
RN [35]
RP VARIANTS CHONGQING ARG-3 AND HARBIN MET-17.
RX PubMed=6526652;
RA Zeng Y.-T., Huang S.-Z., Qiu X.-K., Cheng G.-C., Ren Z.-R., Jin Q.-C.,
RA Chen C.-Y., Jiao C.-T., Tang Z.-G., Liu R.-H., Bao X.-H., Zeng L.-Z.,
RA Duan Y.-Q., Zhang G.-Y.;
RT "Hemoglobin Chongqing [alpha 2(NA2)Leu-->Arg] and hemoglobin Harbin
RT [alpha 16(A14)Lys-->Met] found in China.";
RL Hemoglobin 8:569-581(1984).
RN [36]
RP VARIANT CLINIC LYS-61 DEL.
RX PubMed=10206681;
RX DOI=10.1002/(SICI)1098-1004(1998)11:5<412::AID-HUMU14>3.3.CO;2-I;
RA Ayala S., Colomer D., Gelpi J.L., Corron J.L.V.;
RT "Alpha-thalassaemia due to a single codon deletion in the alpha 1-
RT globin gene. Computational structural analysis of the new alpha-chain
RT variant.";
RL Hum. Mutat. 11:412-412(1998).
RN [37]
RP VARIANT DAVENPORT HIS-79.
RX PubMed=2101836;
RA Wilson J.B., Webber B.B., Plaseska D., de Alarcon P.A., McMillan S.K.,
RA Huisman T.H.J.;
RT "Hb Davenport or alpha 2(78)(EF7)Asn-->His beta 2.";
RL Hemoglobin 14:599-605(1990).
RN [38]
RP VARIANT EVANS MET-63.
RX PubMed=2606724;
RA Wilson J.B., Webber B.B., Kutlar A., Reese A.L., McKie V.C.,
RA Lutcher C.L., Felice A.E., Huisman T.H.J.;
RT "Hb Evans or alpha 262(E11)Val-->Met beta 2; an unstable hemoglobin
RT causing a mild hemolytic anemia.";
RL Hemoglobin 13:557-566(1989).
RN [39]
RP VARIANTS SPANISH TOWN VAL-28 AND FORT DE FRANCE ARG-46.
RX PubMed=2752146;
RA Cash F.E., Monplaisir N., Goossens M., Liebhaber S.A.;
RT "Locus assignment of two alpha-globin structural mutants from the
RT Caribbean basin: alpha Fort de France (alpha 45 Arg) and alpha Spanish
RT Town (alpha 27 Val).";
RL Blood 74:833-835(1989).
RN [40]
RP VARIANT GODAVARI THR-96.
RX PubMed=9494044;
RA Wajcman H., Kister J., Riou J., Galacteros F., Girot R.,
RA Maier-Redelsperger M., Nayudu N.V.S., Giordano P.C.;
RT "Hb Godavari [alpha 95(G2)Pro-->Thr]: a neutral amino acid
RT substitution in the alpha 1 beta 2 interface that modifies the
RT electrophoretic mobility of hemoglobin.";
RL Hemoglobin 22:11-22(1998).
RN [41]
RP VARIANT GRADY GLU-PHE-THR-119 INS.
RX PubMed=4528583; DOI=10.1073/pnas.71.8.3270;
RA Huisman T.H.J., Wilson J.B., Gravely M., Hubbard M.;
RT "Hemoglobin Grady: the first example of a variant with elongated
RT chains due to an insertion of residues.";
RL Proc. Natl. Acad. Sci. U.S.A. 71:3270-3273(1974).
RN [42]
RP VARIANT HANAMAKI GLU-140.
RX PubMed=1634363;
RA Orisaka M., Tajima T., Harano T., Harano K., Kushida Y., Imai K.;
RT "A new alpha chain variant, Hb Hanamaki or alpha 2(139)(HC1)Lys-->Glu
RT beta 2, found in a Japanese family.";
RL Hemoglobin 16:67-71(1992).
RN [43]
RP VARIANT HANDA MET-91.
RX PubMed=6815131;
RA Harano T., Harano K., Shibata S., Ueda S., Imai K., Seki M.;
RT "HB Handa [alpha 90 (FG 2) Lys replaced by Met]: structure and
RT biosynthesis of a new slightly higher oxygen affinity variant.";
RL Hemoglobin 6:379-389(1982).
RN [44]
RP VARIANT HASHARON HIS-48.
RX PubMed=5780195; DOI=10.1172/JCI106041;
RA Charache S., Mondzac A.M., Gessner U.;
RT "Hemoglobin Hasharon (alpha-2-47 his(CD5)beta-2): a hemoglobin found
RT in low concentration.";
RL J. Clin. Invest. 48:834-847(1969).
RN [45]
RP VARIANT HOBART ARG-21.
RX PubMed=3654264;
RA Fleming P.J., Sumner D.R., Wyatt K., Hughes W.G., Melrose W.D.,
RA Jupe D.M.D., Baikie M.J.;
RT "Hemoglobin Hobart or alpha 20(Bl)His-->Arg: a new alpha chain
RT hemoglobin variant.";
RL Hemoglobin 11:211-220(1987).
RN [46]
RP VARIANT INKSTER VAL-86.
RX PubMed=4212045; DOI=10.1111/j.1365-2141.1974.tb00489.x;
RA Reed R.E., Winter W.P., Rucknagel D.L.;
RT "Haemoglobin Inkster (alpha2 85aspartic acid leads to valine beta2)
RT coexisting with beta-thalassaemia in a Caucasian family.";
RL Br. J. Haematol. 26:475-484(1974).
RN [47]
RP VARIANT KANAGAWA MET-41.
RX PubMed=1634355;
RA Miyashita H., Hashimoto K., Mohri H., Ohokubo T., Harano T.,
RA Harano K., Imai K.;
RT "Hb Kanagawa [alpha 40(C5)Lys-->Met]: a new alpha chain variant with
RT an increased oxygen affinity.";
RL Hemoglobin 16:1-10(1992).
RN [48]
RP VARIANT KURDISTAN TYR-48.
RX PubMed=8195005;
RA Giordano P.C., Harteveld C.L., Streng H., Oosterwijk J.C.,
RA Heister J.G.A.M., Amons R., Bernini L.F.;
RT "Hb Kurdistan [alpha 47(CE5)Asp-->Tyr], a new alpha chain variant in
RT combination with beta (0)-thalassemia.";
RL Hemoglobin 18:11-18(1994).
RN [49]
RP VARIANT KUROSAKI GLU-8.
RX PubMed=7558876;
RA Harano T., Harano K., Imai K., Murakami T., Matsubara H.;
RT "Hb Kurosaki [alpha 7(A5)Lys-->Glu]: a new alpha chain variant found
RT in a Japanese woman.";
RL Hemoglobin 19:197-201(1995).
RN [50]
RP VARIANT J-MEERUT/J-BIRMINGHAM GLU-121.
RX PubMed=7713747;
RA Yalcin A., Avcu F., Beyan C., Guergey A., Ural A.U.;
RT "A case of HB J-Meerut (or Hb J-Birmingham) [alpha
RT 120(H3)Ala-->Glu].";
RL Hemoglobin 18:433-435(1994).
RN [51]
RP VARIANT MELUSINE SER-115.
RX PubMed=8294199;
RA Wacjman H., Klames G., Groff P., Prome D., Riou J., Galacteros F.;
RT "Hb Melusine [alpha 114(GH2)Pro-->Ser]: a new neutral hemoglobin
RT variant.";
RL Hemoglobin 17:397-405(1993).
RN [52]
RP VARIANT MONTGOMERY ARG-49.
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 [53]
RP VARIANT PETAH TIKVA ASP-111.
RX PubMed=7470621;
RA Honig G.R., Shamsuddin M., Zaizov R., Steinherz M., Solar I.,
RA Kirschman C.;
RT "Hemoglobin Petah Tikva (alpha 110 Ala replaced by Asp): a new
RT unstable variant with alpha-thalassemia-like expression.";
RL Blood 57:705-711(1981).
RN [54]
RP VARIANT PHNOM PENH ILE-118 INS.
RX PubMed=9452028;
RA Wajcman H., Prehu M.O., Prehu C., Blouquit Y., Prome D.,
RA Galacteros F.;
RT "Hemoglobin Phnom Penh [alpha117Phe(H1)-Ile-alpha118Thr(H2)]; evidence
RT for a hotspot for insertion of residues in the third exon of the
RT alpha1-globin gene.";
RL Hum. Mutat. Suppl. 1:S20-S22(1998).
RN [55]
RP VARIANT PORT HURON ARG-57.
RX PubMed=1802882;
RA Zwerdling T., Williams S., Nasr S.A., Rucknagel D.L.;
RT "Hb Port Huron [alpha 56 (E5)Lys-->Arg]: a new alpha chain variant.";
RL Hemoglobin 15:381-391(1991).
RN [56]
RP VARIANT SAWARA ALA-7.
RX PubMed=4744335;
RA Sumida I., Ohta Y., Imamura T., Yanase T.;
RT "Hemoglobin Sawara: alpha 6(A4) aspartic acid leads to alanine.";
RL Biochim. Biophys. Acta 322:23-26(1973).
RN [57]
RP VARIANT SHENYANG GLU-27.
RX PubMed=7161109;
RA Zeng Y.-T., Huang S.-Z., Zhou X., Qiu X.-K., Dong Q., Li M., Bai J.;
RT "Hb Shenyang (alpha 26 (B7) Ala replaced by Glu): a new unstable
RT variant found in China.";
RL Hemoglobin 6:625-628(1982).
RN [58]
RP VARIANT SUAN-DOK ARG-110.
RX PubMed=478977;
RA Sanguansermsri T., Matragoon S., Changloah L., Flatz G.;
RT "Hemoglobin Suan-Dok (alpha 2 109 (G16) Leu replaced by Arg beta 2):
RT an unstable variant associated with alpha-thalassemia.";
RL Hemoglobin 3:161-174(1979).
RN [59]
RP INVOLVEMENT IN HEIBAN, AND VARIANT TOYAMA ARG-137.
RX PubMed=2833478;
RA Ohba Y., Yamamoto K., Hattori Y., Kawata R., Miyaji T.;
RT "Hyperunstable hemoglobin Toyama [alpha 2 136(H19)Leu----Arg beta 2]:
RT detection and identification by in vitro biosynthesis with radioactive
RT amino acids.";
RL Hemoglobin 11:539-556(1987).
RN [60]
RP VARIANT SUN PRAIRIE PRO-131.
RX PubMed=2079430;
RA Harkness M., Harkness D.R., Kutlar F., Kutlar A., Wilson J.B.,
RA Webber B.B., Codrington J.F., Huisman T.H.J.;
RT "Hb Sun Prairie or alpha(2)130(H13)Ala-->Pro beta 2, a new unstable
RT variant occurring in low quantities.";
RL Hemoglobin 14:479-489(1990).
RN [61]
RP VARIANT SWAN RIVER GLY-7.
RX PubMed=8745434;
RA Harano T., Harano K., Imai K., Terunuma S.;
RT "HB Swan River [alpha 6(A4)Asp-->Gly] observed in a Japanese man.";
RL Hemoglobin 20:75-78(1996).
RN [62]
RP VARIANT THIONVILLE GLU-2.
RX PubMed=1618774;
RA Vasseur C., Blouquit Y., Kister J., Prome D., Kavanaugh J.S.,
RA Rogers P.H., Guillemin C., Arnone A., Galacteros F., Poyart C.,
RA Rosa J., Wajcman H.;
RT "Hemoglobin Thionville. An alpha-chain variant with a substitution of
RT a glutamate for valine at NA-1 and having an acetylated methionine NH2
RT terminus.";
RL J. Biol. Chem. 267:12682-12691(1992).
RN [63]
RP VARIANT TUNIS-BIZERTE PRO-130.
RX PubMed=7786798; DOI=10.1111/j.1365-2141.1995.tb03382.x;
RA Darbellay R., Mach-Pascual S., Rose K., Graf J., Beris P.;
RT "Haemoglobin Tunis-Bizerte: a new alpha 1 globin 129 Leu-->Pro
RT unstable variant with thalassaemic phenotype.";
RL Br. J. Haematol. 90:71-76(1995).
RN [64]
RP VARIANT TURRIFF GLU-100.
RX PubMed=1634357;
RA Langdown J.V., Davidson R.J., Williamson D.;
RT "A new alpha chain variant, Hb Turriff [alpha 99(G6)Lys-->Glu]: the
RT interference of abnormal hemoglobins in Hb A1c determination.";
RL Hemoglobin 16:11-17(1992).
RN [65]
RP VARIANT VAL DE MARNE ARG-134.
RX PubMed=8294200;
RA Wacjman H., Kister J., M'Rad A., Marden M.C., Riou J., Galacteros F.;
RT "Hb Val de Marne [alpha 133(H16)Ser-->Arg]: a new hemoglobin variant
RT with moderate increase in oxygen affinity.";
RL Hemoglobin 17:407-417(1993).
RN [66]
RP VARIANT WESTMEAD GLN-123.
RX PubMed=1686260;
RA Jiang N.H., Liang S., Wen X.J., Liang R., Su C., Tang Z.;
RT "Hb Westmead: an alpha 2-globin gene mutation detected by polymerase
RT chain reaction and Stu I cleavage.";
RL Hemoglobin 15:291-295(1991).
RN [67]
RP VARIANT WOODVILLE TYR-7.
RX PubMed=3754246;
RA Como P.F., Barber S., Sage R.E., Kronenberg H.;
RT "Hemoglobin Woodville: alpha (2)6(A4) aspartic acid-->tyrosine.";
RL Hemoglobin 10:135-141(1986).
RN [68]
RP VARIANT YUDA ASP-131.
RX PubMed=1428950;
RA Fujisawa K., Hattori Y., Ohba Y., Ando S.;
RT "Hb Yuda or alpha 130(H13)Ala-->Asp; a new alpha chain variant with
RT low oxygen affinity.";
RL Hemoglobin 16:435-439(1992).
RN [69]
RP VARIANT ZAIRE HIS-LEU-PRO-ALA-GLU-117 INS.
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 [70]
RP VARIANT HBH VAL-63 DEL.
RX PubMed=10569720;
RA Traeger-Synodinos J., Harteveld C.L., Kanavakis E., Giordano P.C.,
RA Kattamis C., Bernini L.F.;
RT "Hb Aghia Sophia [alpha62(E11)Val-->0 (alpha1)], an 'in-frame'
RT deletion causing alpha-thalassemia.";
RL Hemoglobin 23:317-324(1999).
RN [71]
RP VARIANT BOGHE GLN-59, AND VARIANT CHAROLLES TYR-104.
RX PubMed=10569723;
RA Lacan P., Francina A., Souillet G., Aubry M., Couprie N.,
RA Dementhon L., Becchi M.;
RT "Two new alpha chain variants: Hb Boghe [alpha58(E7)His-->Gln,
RT alpha2], a variant on the distal histidine, and Hb Charolles
RT [alpha103(G10)His-Tyr, alpha1].";
RL Hemoglobin 23:345-352(1999).
RN [72]
RP VARIANT CAMPINAS VAL-27, AND VARIANT WEST ONE GLY-127.
RX PubMed=14576901; DOI=10.1590/S0100-879X2003001100004;
RA Jorge S.B., Melo M.B., Costa F.F., Sonati M.F.;
RT "Screening for mutations in human alpha-globin genes by nonradioactive
RT single-strand conformation polymorphism.";
RL Braz. J. Med. Biol. Res. 36:1471-1474(2003).
RN [73]
RP VARIANT BASSETT ALA-95, AND CHARACTERIZATION OF VARIANT BASSETT
RP ALA-95.
RX PubMed=15495251; DOI=10.1002/ajh.20184;
RA Abdulmalik O., Safo M.K., Lerner N.B., Ochotorena J., Daikhin E.,
RA Lakka V., Santacroce R., Abraham D.J., Asakura T.;
RT "Characterization of hemoglobin Bassett (alpha94Asp-->Ala), a variant
RT with very low oxygen affinity.";
RL Am. J. Hematol. 77:268-276(2004).
RN [74]
RP VARIANT PLASENCIA ARG-126.
RX PubMed=15921163; DOI=10.1081/HEM-200058578;
RA Martin G., Villegas A., Gonzalez F.A., Ropero P., Hojas R., Polo M.,
RA Mateo M., Salvador M., Benavente C.;
RT "A novel mutation of the alpha2-globin causing alpha(+)-thalassemia:
RT Hb Plasencia [alpha125(H8)Leu-->Arg (alpha2).";
RL Hemoglobin 29:113-117(2005).
CC -!- FUNCTION: Involved in oxygen transport from the lung to the
CC various peripheral tissues.
CC -!- SUBUNIT: Heterotetramer of two alpha chains and two beta chains in
CC adult hemoglobin A (HbA); two alpha chains and two delta chains in
CC adult hemoglobin A2 (HbA2); two alpha chains and two epsilon
CC chains in early embryonic hemoglobin Gower-2; two alpha chains and
CC two gamma chains in fetal hemoglobin F (HbF).
CC -!- INTERACTION:
CC P68871:HBB; NbExp=19; IntAct=EBI-714680, EBI-715554;
CC -!- TISSUE SPECIFICITY: Red blood cells.
CC -!- PTM: The initiator Met is not cleaved in variant Thionville and is
CC acetylated.
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: Alpha-thalassemia (A-THAL) [MIM:604131]: A form of
CC thalassemia. Thalassemias are common monogenic diseases occurring
CC mostly in Mediterranean and Southeast Asian populations. The
CC hallmark of alpha-thalassemia is an imbalance in globin-chain
CC production in the adult HbA molecule. The level of alpha chain
CC production can range from none to very nearly normal levels.
CC Deletion of both copies of each of the two alpha-globin genes
CC causes alpha(0)-thalassemia, also known as homozygous alpha
CC thalassemia. Due to the complete absence of alpha chains, the
CC predominant fetal hemoglobin is a tetramer of gamma-chains (Bart
CC hemoglobin) that has essentially no oxygen carrying capacity. This
CC causes oxygen starvation in the fetal tissues leading to prenatal
CC lethality or early neonatal death. The loss of two alpha genes
CC results in mild alpha-thalassemia, also known as heterozygous
CC alpha-thalassemia. Affected individuals have small red cells and a
CC mild anemia (microcytosis). If three of the four alpha-globin
CC genes are functional, individuals are completely asymptomatic.
CC Some rare forms of alpha-thalassemia are due to point mutations
CC (non-deletional alpha-thalassemia). Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Alpha(0)-thalassemia is associated with non-immune
CC hydrops fetalis, a generalized edema of the fetus with fluid
CC accumulation in the body cavities due to non-immune causes. Non-
CC immune hydrops fetalis is not a diagnosis in itself but a symptom,
CC a feature of many genetic disorders, and the end-stage of a wide
CC variety of disorders.
CC -!- DISEASE: Hemoglobin H disease (HBH) [MIM:613978]: A form of alpha-
CC thalassemia due to the loss of three alpha genes. This results in
CC high levels of a tetramer of four beta chains (hemoglobin H),
CC causing a severe and life-threatening anemia. Untreated, most
CC patients die in childhood or early adolescence. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Gives blood its red color.
CC -!- SIMILARITY: Belongs to the globin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD97112.1; Type=Erroneous initiation;
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;=HBA1";
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;=HBA2";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HBA1";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HBA2";
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;=HBA1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hemoglobin entry;
CC URL="http://en.wikipedia.org/wiki/Hemoglobin";
CC -----------------------------------------------------------------------
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DR EMBL; J00153; AAB59407.1; -; Genomic_DNA.
DR EMBL; J00153; AAB59408.1; -; Genomic_DNA.
DR EMBL; V00491; CAA23750.1; -; Genomic_DNA.
DR EMBL; V00493; CAA23752.1; -; mRNA.
DR EMBL; V00488; CAA23748.1; -; Genomic_DNA.
DR EMBL; V00516; CAA23774.1; -; Genomic_DNA.
DR EMBL; AF230076; AAF72612.1; -; Genomic_DNA.
DR EMBL; AF525460; AAM83102.1; -; Genomic_DNA.
DR EMBL; DQ431198; ABD95910.1; -; Genomic_DNA.
DR EMBL; DQ431198; ABD95911.1; -; Genomic_DNA.
DR EMBL; AF097635; AAC72839.1; -; mRNA.
DR EMBL; AF105974; AAC97373.1; -; mRNA.
DR EMBL; AF349571; AAK37554.1; -; mRNA.
DR EMBL; AF536204; AAN04486.1; -; Genomic_DNA.
DR EMBL; DQ499017; ABF56144.1; -; Genomic_DNA.
DR EMBL; DQ499018; ABF56145.1; -; Genomic_DNA.
DR EMBL; AK223392; BAD97112.1; ALT_INIT; mRNA.
DR EMBL; AE006462; AAK61215.1; -; Genomic_DNA.
DR EMBL; AE006462; AAK61216.1; -; Genomic_DNA.
DR EMBL; Z84721; CAB06554.1; -; Genomic_DNA.
DR EMBL; Z84721; CAB06555.1; -; Genomic_DNA.
DR EMBL; BC005931; AAH05931.1; -; mRNA.
DR EMBL; BC008572; AAH08572.1; -; mRNA.
DR EMBL; BC032122; AAH32122.1; -; mRNA.
DR EMBL; BC050661; AAH50661.1; -; mRNA.
DR EMBL; BC101846; AAI01847.1; -; mRNA.
DR EMBL; BC101848; AAI01849.1; -; mRNA.
DR PIR; A90807; HAHU.
DR PIR; C93303; HACZP.
DR PIR; I58217; HACZ.
DR RefSeq; NP_000508.1; NM_000517.4.
DR RefSeq; NP_000549.1; NM_000558.3.
DR UniGene; Hs.449630; -.
DR UniGene; Hs.654744; -.
DR PDB; 1A00; X-ray; 2.00 A; A/C=2-142.
DR PDB; 1A01; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1A0U; X-ray; 2.14 A; A/C=2-142.
DR PDB; 1A0Z; X-ray; 2.00 A; A/C=2-142.
DR PDB; 1A3N; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1A3O; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1A9W; X-ray; 2.90 A; A/C=2-142.
DR PDB; 1ABW; X-ray; 2.00 A; A=2-142.
DR PDB; 1ABY; X-ray; 2.60 A; A=2-142.
DR PDB; 1AJ9; X-ray; 2.20 A; A=2-142.
DR PDB; 1B86; X-ray; 2.50 A; A/C=2-142.
DR PDB; 1BAB; X-ray; 1.50 A; A/C=3-142.
DR PDB; 1BBB; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1BIJ; X-ray; 2.30 A; A/C=2-142.
DR PDB; 1BUW; X-ray; 1.90 A; A/C=2-142.
DR PDB; 1BZ0; X-ray; 1.50 A; A/C=2-142.
DR PDB; 1BZ1; X-ray; 1.59 A; A/C=2-142.
DR PDB; 1BZZ; X-ray; 1.59 A; A/C=3-142.
DR PDB; 1C7B; X-ray; 1.80 A; A/C=3-142.
DR PDB; 1C7C; X-ray; 1.80 A; A=2-142.
DR PDB; 1C7D; X-ray; 1.80 A; A=2-142.
DR PDB; 1CLS; X-ray; 1.90 A; A/C=2-142.
DR PDB; 1CMY; X-ray; 3.00 A; A/C=2-142.
DR PDB; 1COH; X-ray; 2.90 A; A/C=2-142.
DR PDB; 1DKE; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1DXT; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1DXU; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1DXV; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1FDH; X-ray; 2.50 A; A/B=2-142.
DR PDB; 1FN3; X-ray; 2.48 A; A/C=2-142.
DR PDB; 1G9V; X-ray; 1.85 A; A/C=2-142.
DR PDB; 1GBU; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1GBV; X-ray; 2.00 A; A/C=2-142.
DR PDB; 1GLI; X-ray; 2.50 A; A/C=3-142.
DR PDB; 1GZX; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1HAB; X-ray; 2.30 A; A/C=2-142.
DR PDB; 1HAC; X-ray; 2.60 A; A/C=2-142.
DR PDB; 1HBA; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1HBB; X-ray; 1.90 A; A/C=2-142.
DR PDB; 1HBS; X-ray; 3.00 A; A/C/E/G=2-141.
DR PDB; 1HCO; X-ray; 2.70 A; A=2-142.
DR PDB; 1HDB; X-ray; 2.20 A; A/C=2-142.
DR PDB; 1HGA; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1HGB; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1HGC; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1HHO; X-ray; 2.10 A; A=2-141.
DR PDB; 1IRD; X-ray; 1.25 A; A=2-142.
DR PDB; 1J3Y; X-ray; 1.55 A; A/C/E/G=2-142.
DR PDB; 1J3Z; X-ray; 1.60 A; A/C/E/G=2-142.
DR PDB; 1J40; X-ray; 1.45 A; A/C/E/G=2-142.
DR PDB; 1J41; X-ray; 1.45 A; A/C/E/G=2-142.
DR PDB; 1J7S; X-ray; 2.20 A; A/C=3-142.
DR PDB; 1J7W; X-ray; 2.00 A; A/C=3-142.
DR PDB; 1J7Y; X-ray; 1.70 A; A/C=3-142.
DR PDB; 1JY7; X-ray; 3.20 A; A/C/P/R/U/W=2-142.
DR PDB; 1K0Y; X-ray; 1.87 A; A/C=2-142.
DR PDB; 1K1K; X-ray; 2.00 A; A=2-142.
DR PDB; 1KD2; X-ray; 1.87 A; A/C=2-142.
DR PDB; 1LFL; X-ray; 2.70 A; A/C/P/R=2-142.
DR PDB; 1LFQ; X-ray; 2.60 A; A=2-142.
DR PDB; 1LFT; X-ray; 2.60 A; A=2-142.
DR PDB; 1LFV; X-ray; 2.80 A; A=2-142.
DR PDB; 1LFY; X-ray; 3.30 A; A=2-142.
DR PDB; 1LFZ; X-ray; 3.10 A; A=2-142.
DR PDB; 1LJW; X-ray; 2.16 A; A=2-142.
DR PDB; 1M9P; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1MKO; X-ray; 2.18 A; A/C=2-142.
DR PDB; 1NEJ; X-ray; 2.10 A; A/C=2-142.
DR PDB; 1NIH; X-ray; 2.60 A; A/C=2-142.
DR PDB; 1NQP; X-ray; 1.73 A; A/C=2-142.
DR PDB; 1O1I; X-ray; 2.30 A; A=2-142.
DR PDB; 1O1J; X-ray; 1.90 A; A=2-142.
DR PDB; 1O1K; X-ray; 2.00 A; A/C=3-142.
DR PDB; 1O1L; X-ray; 1.80 A; A=2-142.
DR PDB; 1O1M; X-ray; 1.85 A; A=2-142.
DR PDB; 1O1N; X-ray; 1.80 A; A=2-142.
DR PDB; 1O1O; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1O1P; X-ray; 1.80 A; A=2-142.
DR PDB; 1QI8; X-ray; 1.80 A; A/C=3-142.
DR PDB; 1QSH; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1QSI; X-ray; 1.70 A; A/C=2-142.
DR PDB; 1QXD; X-ray; 2.25 A; A/C=2-142.
DR PDB; 1QXE; X-ray; 1.85 A; A/C=2-142.
DR PDB; 1R1X; X-ray; 2.15 A; A=2-142.
DR PDB; 1R1Y; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1RPS; X-ray; 2.11 A; A/C=2-142.
DR PDB; 1RQ3; X-ray; 1.91 A; A/C=2-142.
DR PDB; 1RQ4; X-ray; 2.11 A; A/C=2-142.
DR PDB; 1RQA; X-ray; 2.11 A; A/C=2-141.
DR PDB; 1RVW; X-ray; 2.50 A; A=2-142.
DR PDB; 1SDK; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1SDL; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1SHR; X-ray; 1.88 A; A/C=2-142.
DR PDB; 1SI4; X-ray; 2.20 A; A/C=2-142.
DR PDB; 1THB; X-ray; 1.50 A; A/C=2-142.
DR PDB; 1UIW; X-ray; 1.50 A; A/C/E/G=2-142.
DR PDB; 1VWT; X-ray; 1.90 A; A/C=2-141.
DR PDB; 1XXT; X-ray; 1.91 A; A/C=2-142.
DR PDB; 1XY0; X-ray; 1.99 A; A/C=3-142.
DR PDB; 1XYE; X-ray; 2.13 A; A/C=3-142.
DR PDB; 1XZ2; X-ray; 1.90 A; A/C=1-142.
DR PDB; 1XZ4; X-ray; 2.00 A; A/C=3-142.
DR PDB; 1XZ5; X-ray; 2.11 A; A/C=3-142.
DR PDB; 1XZ7; X-ray; 1.90 A; A/C=3-142.
DR PDB; 1XZU; X-ray; 2.16 A; A/C=3-142.
DR PDB; 1XZV; X-ray; 2.11 A; A/C=3-142.
DR PDB; 1Y01; X-ray; 2.80 A; B=2-141.
DR PDB; 1Y09; X-ray; 2.25 A; A/C=3-142.
DR PDB; 1Y0A; X-ray; 2.22 A; A/C=3-142.
DR PDB; 1Y0C; X-ray; 2.30 A; A/C=3-142.
DR PDB; 1Y0D; X-ray; 2.10 A; A/C=2-140.
DR PDB; 1Y0T; X-ray; 2.14 A; A/C=1-142.
DR PDB; 1Y0W; X-ray; 2.14 A; A/C=1-142.
DR PDB; 1Y22; X-ray; 2.16 A; A/C=1-142.
DR PDB; 1Y2Z; X-ray; 2.07 A; A/C=1-142.
DR PDB; 1Y31; X-ray; 2.13 A; A/C=2-141.
DR PDB; 1Y35; X-ray; 2.12 A; A/C=1-142.
DR PDB; 1Y45; X-ray; 2.00 A; A/C=1-142.
DR PDB; 1Y46; X-ray; 2.22 A; A/C=2-141.
DR PDB; 1Y4B; X-ray; 2.10 A; A/C=1-142.
DR PDB; 1Y4F; X-ray; 2.00 A; A/C=2-141.
DR PDB; 1Y4G; X-ray; 1.91 A; A/C=2-141.
DR PDB; 1Y4P; X-ray; 1.98 A; A/C=2-141.
DR PDB; 1Y4Q; X-ray; 2.11 A; A/C=1-142.
DR PDB; 1Y4R; X-ray; 2.22 A; A/C=1-142.
DR PDB; 1Y4V; X-ray; 1.84 A; A/C=1-142.
DR PDB; 1Y5F; X-ray; 2.14 A; A/C=1-142.
DR PDB; 1Y5J; X-ray; 2.03 A; A/C=1-142.
DR PDB; 1Y5K; X-ray; 2.20 A; A/C=1-142.
DR PDB; 1Y7C; X-ray; 2.10 A; A/C=1-142.
DR PDB; 1Y7D; X-ray; 1.90 A; A/C=1-142.
DR PDB; 1Y7G; X-ray; 2.10 A; A/C=1-142.
DR PDB; 1Y7Z; X-ray; 1.98 A; A/C=1-142.
DR PDB; 1Y83; X-ray; 1.90 A; A/C=1-142.
DR PDB; 1Y85; X-ray; 2.13 A; A/C=2-141.
DR PDB; 1Y8W; X-ray; 2.90 A; A/C=3-142.
DR PDB; 1YDZ; X-ray; 3.30 A; A/C=3-142.
DR PDB; 1YE0; X-ray; 2.50 A; A/C=1-142.
DR PDB; 1YE1; X-ray; 4.50 A; A/C=1-142.
DR PDB; 1YE2; X-ray; 1.80 A; A/C=1-142.
DR PDB; 1YEN; X-ray; 2.80 A; A/C=1-142.
DR PDB; 1YEO; X-ray; 2.22 A; A/C=1-142.
DR PDB; 1YEQ; X-ray; 2.75 A; A/C=1-142.
DR PDB; 1YEU; X-ray; 2.12 A; A/C=1-142.
DR PDB; 1YEV; X-ray; 2.11 A; A/C=1-142.
DR PDB; 1YFF; X-ray; 2.40 A; A/C/E/G=2-142.
DR PDB; 1YG5; X-ray; 2.70 A; A/C=1-142.
DR PDB; 1YGD; X-ray; 2.73 A; A/C=1-142.
DR PDB; 1YGF; X-ray; 2.70 A; A/C=1-142.
DR PDB; 1YH9; X-ray; 2.20 A; A/C=1-142.
DR PDB; 1YHE; X-ray; 2.10 A; A/C=1-142.
DR PDB; 1YHR; X-ray; 2.60 A; A/C=1-142.
DR PDB; 1YIE; X-ray; 2.40 A; A/C=1-142.
DR PDB; 1YIH; X-ray; 2.00 A; A/C=1-142.
DR PDB; 1YVQ; X-ray; 1.80 A; A/C=2-142.
DR PDB; 1YVT; X-ray; 1.80 A; A=1-142.
DR PDB; 1YZI; X-ray; 2.07 A; A=1-142.
DR PDB; 1Z8U; X-ray; 2.40 A; B/D=1-142.
DR PDB; 2D5Z; X-ray; 1.45 A; A/C=1-142.
DR PDB; 2D60; X-ray; 1.70 A; A/C=1-142.
DR PDB; 2DN1; X-ray; 1.25 A; A=2-141.
DR PDB; 2DN2; X-ray; 1.25 A; A/C=2-141.
DR PDB; 2DN3; X-ray; 1.25 A; A=1-142.
DR PDB; 2DXM; Neutron; 2.10 A; A/C=2-142.
DR PDB; 2H35; NMR; -; A=1-142, C=2-142.
DR PDB; 2HBC; X-ray; 2.10 A; A=1-142.
DR PDB; 2HBD; X-ray; 2.20 A; A=2-142.
DR PDB; 2HBE; X-ray; 2.00 A; A=1-142.
DR PDB; 2HBF; X-ray; 2.20 A; A=1-142.
DR PDB; 2HBS; X-ray; 2.05 A; A/C/E/G=1-142.
DR PDB; 2HCO; X-ray; 2.70 A; A=2-142.
DR PDB; 2HHB; X-ray; 1.74 A; A/C=2-142.
DR PDB; 2HHD; X-ray; 2.20 A; A/C=2-142.
DR PDB; 2HHE; X-ray; 2.20 A; A/C=1-142.
DR PDB; 2M6Z; NMR; -; A/C=2-142.
DR PDB; 2W6V; X-ray; 1.80 A; A/C=2-142.
DR PDB; 2W72; X-ray; 1.07 A; A=2-142, C=3-142.
DR PDB; 2YRS; X-ray; 2.30 A; A/C/I/M=2-142.
DR PDB; 3B75; X-ray; 2.30 A; A/C/E/G/S=2-142.
DR PDB; 3D17; X-ray; 2.80 A; A/C=2-142.
DR PDB; 3D7O; X-ray; 1.80 A; A=2-142.
DR PDB; 3DUT; X-ray; 1.55 A; A/C=2-142.
DR PDB; 3HHB; X-ray; 1.74 A; A/C=2-142.
DR PDB; 3HXN; X-ray; 2.00 A; A/C=2-142.
DR PDB; 3IA3; X-ray; 3.20 A; B/D=2-142.
DR PDB; 3IC0; X-ray; 1.80 A; A/C=2-141.
DR PDB; 3IC2; X-ray; 2.40 A; A/C=2-142.
DR PDB; 3KMF; Neutron; 2.00 A; A/E=2-142.
DR PDB; 3NL7; X-ray; 1.80 A; A=2-142.
DR PDB; 3NMM; X-ray; 1.60 A; A/C=2-142.
DR PDB; 3ODQ; X-ray; 3.10 A; A/C=2-142.
DR PDB; 3ONZ; X-ray; 2.09 A; A=2-142.
DR PDB; 3OO4; X-ray; 1.90 A; A=2-142.
DR PDB; 3OO5; X-ray; 2.10 A; A=2-142.
DR PDB; 3OVU; X-ray; 2.83 A; C=2-142.
DR PDB; 3P5Q; X-ray; 2.00 A; A=2-142.
DR PDB; 3QJB; X-ray; 1.80 A; A=2-142.
DR PDB; 3QJC; X-ray; 2.00 A; A=2-142.
DR PDB; 3QJD; X-ray; 1.56 A; A/C=2-142.
DR PDB; 3QJE; X-ray; 1.80 A; A/C=2-142.
DR PDB; 3R5I; X-ray; 2.20 A; A/C=2-142.
DR PDB; 3S48; X-ray; 3.05 A; C/D=2-142.
DR PDB; 3S65; X-ray; 1.80 A; A/C=2-142.
DR PDB; 3S66; X-ray; 1.40 A; A=2-142.
DR PDB; 3SZK; X-ray; 3.01 A; A/D=2-142.
DR PDB; 3WCP; X-ray; 1.94 A; A/C=2-142.
DR PDB; 4FC3; X-ray; 2.26 A; A=2-142.
DR PDB; 4HHB; X-ray; 1.74 A; A/C=1-142.
DR PDB; 4L7Y; X-ray; 1.80 A; A/C=2-142.
DR PDB; 4MQC; X-ray; 2.20 A; A=2-142.
DR PDB; 4MQG; X-ray; 1.68 A; A=2-142.
DR PDB; 4MQH; X-ray; 2.50 A; A=2-140.
DR PDB; 4MQI; X-ray; 1.92 A; A=2-141.
DR PDB; 4MQJ; X-ray; 1.80 A; A/C/E/G=2-142.
DR PDB; 4MQK; X-ray; 2.24 A; A/C/E/G=2-142.
DR PDB; 6HBW; X-ray; 2.00 A; A/C=1-142.
DR PDBsum; 1A00; -.
DR PDBsum; 1A01; -.
DR PDBsum; 1A0U; -.
DR PDBsum; 1A0Z; -.
DR PDBsum; 1A3N; -.
DR PDBsum; 1A3O; -.
DR PDBsum; 1A9W; -.
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; 1CLS; -.
DR PDBsum; 1CMY; -.
DR PDBsum; 1COH; -.
DR PDBsum; 1DKE; -.
DR PDBsum; 1DXT; -.
DR PDBsum; 1DXU; -.
DR PDBsum; 1DXV; -.
DR PDBsum; 1FDH; -.
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; 1SHR; -.
DR PDBsum; 1SI4; -.
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; 1Y01; -.
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; 1Z8U; -.
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; 3IA3; -.
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; 3OVU; -.
DR PDBsum; 3P5Q; -.
DR PDBsum; 3QJB; -.
DR PDBsum; 3QJC; -.
DR PDBsum; 3QJD; -.
DR PDBsum; 3QJE; -.
DR PDBsum; 3R5I; -.
DR PDBsum; 3S48; -.
DR PDBsum; 3S65; -.
DR PDBsum; 3S66; -.
DR PDBsum; 3SZK; -.
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; 4MQJ; -.
DR PDBsum; 4MQK; -.
DR PDBsum; 6HBW; -.
DR ProteinModelPortal; P69905; -.
DR SMR; P69905; 2-142.
DR DIP; DIP-35199N; -.
DR IntAct; P69905; 19.
DR MINT; MINT-1519936; -.
DR STRING; 9606.ENSP00000251595; -.
DR ChEMBL; CHEMBL2095168; -.
DR DrugBank; DB00613; Amodiaquine.
DR DrugBank; DB00608; Chloroquine.
DR DrugBank; DB00893; Iron Dextran.
DR DrugBank; DB00358; Mefloquine.
DR DrugBank; DB01087; Primaquine.
DR DrugBank; DB00468; Quinine.
DR PhosphoSite; P69905; -.
DR DOSAC-COBS-2DPAGE; P69905; -.
DR REPRODUCTION-2DPAGE; IPI00410714; -.
DR SWISS-2DPAGE; P69905; -.
DR UCD-2DPAGE; P01922; -.
DR UCD-2DPAGE; P69905; -.
DR PaxDb; P69905; -.
DR PeptideAtlas; P69905; -.
DR PRIDE; P69905; -.
DR DNASU; 3039; -.
DR Ensembl; ENST00000251595; ENSP00000251595; ENSG00000188536.
DR Ensembl; ENST00000320868; ENSP00000322421; ENSG00000206172.
DR GeneID; 3039; -.
DR GeneID; 3040; -.
DR KEGG; hsa:3039; -.
DR KEGG; hsa:3040; -.
DR UCSC; uc002cfv.4; human.
DR CTD; 3039; -.
DR CTD; 3040; -.
DR GeneCards; GC16P000291; -.
DR GeneCards; GC16P000292; -.
DR HGNC; HGNC:4823; HBA1.
DR HGNC; HGNC:4824; HBA2.
DR HPA; CAB032534; -.
DR HPA; CAB038417; -.
DR HPA; HPA043780; -.
DR MIM; 140700; phenotype.
DR MIM; 141800; gene+phenotype.
DR MIM; 141850; gene.
DR MIM; 141860; gene.
DR MIM; 604131; phenotype.
DR MIM; 613978; phenotype.
DR neXtProt; NX_P69905; -.
DR Orphanet; 98791; Alpha thalassemia - intellectual deficit syndrome linked to chromosome 16.
DR Orphanet; 330041; Autosomal dominant methemoglobinemia.
DR Orphanet; 163596; Hb Bart's hydrops fetalis.
DR Orphanet; 93616; Hemoglobin H disease.
DR PharmGKB; PA29199; -.
DR eggNOG; NOG283543; -.
DR HOVERGEN; HBG009709; -.
DR InParanoid; P69905; -.
DR KO; K13822; -.
DR OMA; LACHHPA; -.
DR OrthoDB; EOG7KH9MP; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR ChiTaRS; HBA2; human.
DR EvolutionaryTrace; P69905; -.
DR GeneWiki; HBA2; -.
DR GeneWiki; Hemoglobin,_alpha_1; -.
DR GeneWiki; Hemoglobin,_alpha_2; -.
DR NextBio; 12034; -.
DR PMAP-CutDB; P69905; -.
DR PRO; PR:P69905; -.
DR ArrayExpress; P69905; -.
DR Bgee; P69905; -.
DR CleanEx; HS_HBA1; -.
DR CleanEx; HS_HBA2; -.
DR Genevestigator; P69905; -.
DR GO; GO:0022627; C:cytosolic small ribosomal subunit; IDA:UniProtKB.
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; TAS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0019825; F:oxygen binding; IEA:InterPro.
DR GO; GO:0005344; F:oxygen transporter activity; IEA:UniProtKB-KW.
DR GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR GO; GO:0042744; P:hydrogen peroxide catabolic process; IDA:BHF-UCL.
DR GO; GO:0015671; P:oxygen transport; TAS:UniProtKB.
DR GO; GO:0010942; P:positive regulation of cell death; IDA:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IDA:BHF-UCL.
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; IPR002338; Haemoglobin_a.
DR InterPro; IPR018331; Haemoglobin_alpha_chain.
DR InterPro; IPR002339; Haemoglobin_pi.
DR PANTHER; PTHR11442:SF14; PTHR11442:SF14; 1.
DR Pfam; PF00042; Globin; 1.
DR PRINTS; PR00612; ALPHAHAEM.
DR PRINTS; PR00815; PIHAEM.
DR SUPFAM; SSF46458; SSF46458; 1.
DR PROSITE; PS01033; GLOBIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycation; Glycoprotein;
KW Heme; Hereditary hemolytic anemia; Iron; Metal-binding;
KW Oxygen transport; Polymorphism; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 142 Hemoglobin subunit alpha.
FT /FTId=PRO_0000052653.
FT METAL 59 59 Iron (heme distal ligand).
FT METAL 88 88 Iron (heme proximal ligand).
FT SITE 12 12 Not glycated.
FT SITE 57 57 Not glycated.
FT SITE 61 61 Not glycated.
FT SITE 91 91 Not glycated.
FT SITE 100 100 Not glycated.
FT MOD_RES 17 17 N6-acetyllysine; alternate.
FT CARBOHYD 8 8 N-linked (Glc) (glycation).
FT CARBOHYD 17 17 N-linked (Glc) (glycation); alternate.
FT CARBOHYD 41 41 N-linked (Glc) (glycation).
FT CARBOHYD 62 62 N-linked (Glc) (glycation).
FT VARIANT 2 2 V -> E (in Thionville; O(2) affinity
FT down).
FT /FTId=VAR_002719.
FT VARIANT 3 3 L -> R (in ChongQing; O(2) affinity up;
FT dbSNP:rs36030576).
FT /FTId=VAR_002720.
FT VARIANT 6 6 A -> D (in J-Toronto; dbSNP:rs34090856).
FT /FTId=VAR_002721.
FT VARIANT 6 6 A -> P (in Karachi; dbSNP:rs34751764).
FT /FTId=VAR_002722.
FT VARIANT 7 7 D -> A (in Sawara; O(2) affinity up;
FT dbSNP:rs33986902).
FT /FTId=VAR_002723.
FT VARIANT 7 7 D -> G (in Swan River).
FT /FTId=VAR_002724.
FT VARIANT 7 7 D -> N (in Dunn; O(2) affinity up;
FT dbSNP:rs33961916).
FT /FTId=VAR_002725.
FT VARIANT 7 7 D -> V (in Ferndown; O(2) affinity up).
FT /FTId=VAR_002726.
FT VARIANT 7 7 D -> Y (in Woodville; O(2) affinity up).
FT /FTId=VAR_002727.
FT VARIANT 8 8 K -> E (in Kurosaki; dbSNP:rs34817956).
FT /FTId=VAR_002728.
FT VARIANT 10 10 N -> T (in Broomfield).
FT /FTId=VAR_038149.
FT VARIANT 11 11 V -> F (in dbSNP:rs1799896).
FT /FTId=VAR_014605.
FT VARIANT 12 12 K -> E (in Anantharaj).
FT /FTId=VAR_002729.
FT VARIANT 13 13 A -> D (in J-Paris 1/J-Aljezur;
FT dbSNP:rs35615982).
FT /FTId=VAR_002730.
FT VARIANT 14 14 A -> P (in Ravenscourt Park; causes
FT alpha-thalassemia; dbSNP:rs35331909).
FT /FTId=VAR_038150.
FT VARIANT 15 15 W -> R (in Evanston; O(2) affinity up;
FT dbSNP:rs33964317).
FT /FTId=VAR_002731.
FT VARIANT 16 16 G -> R (in Ottawa/Siam;
FT dbSNP:rs35816645).
FT /FTId=VAR_002732.
FT VARIANT 17 17 K -> M (in Harbin; slightly unstable;
FT dbSNP:rs35210126).
FT /FTId=VAR_002733.
FT VARIANT 17 17 K -> N (in Beijing; dbSNP:rs33923844).
FT /FTId=VAR_002734.
FT VARIANT 19 19 G -> D (in Al-Ain Abu Dhabi;
FT dbSNP:rs35993097).
FT /FTId=VAR_002735.
FT VARIANT 19 19 G -> R (in Handsworth; dbSNP:rs34504387).
FT /FTId=VAR_002736.
FT VARIANT 20 20 A -> D (in J-Kurosh).
FT /FTId=VAR_002737.
FT VARIANT 20 20 A -> E (in J-Tashikuergan;
FT dbSNP:rs35628685).
FT /FTId=VAR_002738.
FT VARIANT 21 21 H -> Q (in Le Lamentin;
FT dbSNP:rs41525149).
FT /FTId=VAR_002739.
FT VARIANT 21 21 H -> R (in Hobart; dbSNP:rs33943087).
FT /FTId=VAR_002740.
FT VARIANT 22 22 A -> D (in J-Nyanza; dbSNP:rs11548605).
FT /FTId=VAR_002741.
FT VARIANT 22 22 A -> P (in Fontainebleau;
FT dbSNP:rs34324664).
FT /FTId=VAR_002742.
FT VARIANT 23 23 G -> D (in J-Medellin; dbSNP:rs34608326).
FT /FTId=VAR_002743.
FT VARIANT 24 24 E -> G (in Reims; slightly unstable;
FT dbSNP:rs33939421).
FT /FTId=VAR_002744.
FT VARIANT 24 24 E -> K (in Chad).
FT /FTId=VAR_002745.
FT VARIANT 25 25 Y -> H (in Luxembourg; unstable).
FT /FTId=VAR_002746.
FT VARIANT 27 27 A -> E (in Shenyang; unstable).
FT /FTId=VAR_002747.
FT VARIANT 27 27 A -> V (in Campinas).
FT /FTId=VAR_025387.
FT VARIANT 28 28 E -> D (in Hekinan).
FT /FTId=VAR_002748.
FT VARIANT 28 28 E -> G (in Fort Worth).
FT /FTId=VAR_002749.
FT VARIANT 28 28 E -> V (in Spanish town).
FT /FTId=VAR_002750.
FT VARIANT 31 31 E -> K (in O-Padova).
FT /FTId=VAR_002751.
FT VARIANT 32 32 R -> K (causes alpha-thalassemia).
FT /FTId=VAR_025002.
FT VARIANT 32 32 R -> S (in Prato; unstable).
FT /FTId=VAR_002752.
FT VARIANT 35 35 L -> R (in Queens/Ogi).
FT /FTId=VAR_002753.
FT VARIANT 38 38 P -> PE (in Catonsville).
FT /FTId=VAR_002755.
FT VARIANT 38 38 P -> R (in Bourmedes).
FT /FTId=VAR_002754.
FT VARIANT 41 41 K -> M (in Kanagawa; O(2) affinity up).
FT /FTId=VAR_002756.
FT VARIANT 42 42 T -> S (in Miyano; O(2) affinity up).
FT /FTId=VAR_002757.
FT VARIANT 44 44 F -> L (in Hirosaki; unstable).
FT /FTId=VAR_002758.
FT VARIANT 45 45 P -> L (in Milledgeville; O(2) affinity
FT up; dbSNP:rs41514946).
FT /FTId=VAR_002759.
FT VARIANT 45 45 P -> R (in Kawachi; O(2) affinity up).
FT /FTId=VAR_002760.
FT VARIANT 46 46 H -> Q (in Bari).
FT /FTId=VAR_002761.
FT VARIANT 46 46 H -> R (in Fort de France; O(2) affinity
FT up).
FT /FTId=VAR_002762.
FT VARIANT 48 48 D -> A (in Cordele; unstable).
FT /FTId=VAR_002763.
FT VARIANT 48 48 D -> G (in Umi/Michigan; unstable).
FT /FTId=VAR_002764.
FT VARIANT 48 48 D -> H (in Hasharon/Sinai; unstable).
FT /FTId=VAR_002765.
FT VARIANT 48 48 D -> Y (in Kurdistan).
FT /FTId=VAR_002766.
FT VARIANT 49 49 L -> R (in Montgomery).
FT /FTId=VAR_002767.
FT VARIANT 50 50 S -> R (in Savaria).
FT /FTId=VAR_002768.
FT VARIANT 51 51 H -> R (in Aichi; slightly unstable).
FT /FTId=VAR_002769.
FT VARIANT 52 52 G -> D (in J-Abidjan).
FT /FTId=VAR_002770.
FT VARIANT 52 52 G -> R (in Russ).
FT /FTId=VAR_002771.
FT VARIANT 54 54 A -> D (in J-Rovigo; unstable).
FT /FTId=VAR_002772.
FT VARIANT 55 55 Q -> R (in Hikoshima/Shimonoseki).
FT /FTId=VAR_002773.
FT VARIANT 57 57 K -> R (in Port Huron).
FT /FTId=VAR_002774.
FT VARIANT 57 57 K -> T (in Thailand).
FT /FTId=VAR_002775.
FT VARIANT 58 58 G -> R (in L-Persian Gulf).
FT /FTId=VAR_002776.
FT VARIANT 59 59 H -> Q (in Boghe).
FT /FTId=VAR_025388.
FT VARIANT 59 59 H -> Y (in M-Boston/M-Osaka; O(2)
FT affinity down).
FT /FTId=VAR_002777.
FT VARIANT 60 60 G -> D (in Adana; unstable; causes alpha-
FT thalassemia; dbSNP:rs28928878).
FT /FTId=VAR_002778.
FT VARIANT 60 60 G -> V (in Tottori; unstable).
FT /FTId=VAR_002779.
FT VARIANT 61 61 K -> N (in Zambia; dbSNP:rs28928887).
FT /FTId=VAR_002780.
FT VARIANT 61 61 Missing (in Clinic; unstable; causes
FT alpha-thalassemia).
FT /FTId=VAR_002781.
FT VARIANT 62 62 K -> N (in J-Buda).
FT /FTId=VAR_002782.
FT VARIANT 62 62 K -> T (in J-Anatolia).
FT /FTId=VAR_002783.
FT VARIANT 63 63 V -> M (in Evans; unstable).
FT /FTId=VAR_002784.
FT VARIANT 63 63 Missing (in HBH; hemoglobin Aghia
FT Sophia).
FT /FTId=VAR_066401.
FT VARIANT 64 64 A -> D (in Pontoise; unstable).
FT /FTId=VAR_002785.
FT VARIANT 65 65 D -> Y (in Persepolis).
FT /FTId=VAR_002786.
FT VARIANT 69 69 N -> K (in G-Philadelphia;
FT dbSNP:rs1060339).
FT /FTId=VAR_002787.
FT VARIANT 72 72 A -> E (in J-Habana).
FT /FTId=VAR_002788.
FT VARIANT 72 72 A -> V (in Ozieri).
FT /FTId=VAR_002789.
FT VARIANT 73 73 H -> R (in Daneskgah-Teheran).
FT /FTId=VAR_002790.
FT VARIANT 75 75 D -> A (in Lille).
FT /FTId=VAR_002791.
FT VARIANT 75 75 D -> G (in Chapel Hill).
FT /FTId=VAR_002792.
FT VARIANT 75 75 D -> N (in G-Pest).
FT /FTId=VAR_002793.
FT VARIANT 76 76 D -> A (in Duan).
FT /FTId=VAR_002794.
FT VARIANT 76 76 D -> H (in Q-Iran).
FT /FTId=VAR_002795.
FT VARIANT 77 77 M -> K (in Noko).
FT /FTId=VAR_002796.
FT VARIANT 77 77 M -> T (in Aztec).
FT /FTId=VAR_002797.
FT VARIANT 78 78 P -> R (in Guizhou).
FT /FTId=VAR_002798.
FT VARIANT 79 79 N -> H (in Davenport).
FT /FTId=VAR_002799.
FT VARIANT 79 79 N -> K (in Stanleyville-2).
FT /FTId=VAR_002800.
FT VARIANT 80 80 A -> G (in Singapore).
FT /FTId=VAR_012662.
FT VARIANT 81 81 L -> R (in Ann Arbor; unstable).
FT /FTId=VAR_002801.
FT VARIANT 82 82 S -> C (in Nigeria).
FT /FTId=VAR_002802.
FT VARIANT 83 83 A -> D (in Garden State).
FT /FTId=VAR_002803.
FT VARIANT 85 85 S -> R (in Etobicoke; O(2) affinity up).
FT /FTId=VAR_002804.
FT VARIANT 86 86 D -> V (in Inkster; O(2) affinity up).
FT /FTId=VAR_002805.
FT VARIANT 86 86 D -> Y (in Atago; O(2) affinity up).
FT /FTId=VAR_002806.
FT VARIANT 87 87 L -> R (in Moabit; unstable).
FT /FTId=VAR_002807.
FT VARIANT 88 88 H -> N (in Auckland; unstable).
FT /FTId=VAR_002808.
FT VARIANT 88 88 H -> R (in Iwata; unstable).
FT /FTId=VAR_002809.
FT VARIANT 89 89 A -> S (in Loire; O(2) affinity up).
FT /FTId=VAR_002810.
FT VARIANT 91 91 K -> M (in Handa; O(2) affinity up).
FT /FTId=VAR_002811.
FT VARIANT 92 92 L -> F (in dbSNP:rs17407508).
FT /FTId=VAR_049272.
FT VARIANT 92 92 L -> P (in Port Phillip; unstable;
FT dbSNP:rs17407508).
FT /FTId=VAR_002812.
FT VARIANT 93 93 R -> Q (in J-Cape Town; O(2) affinity
FT up).
FT /FTId=VAR_002813.
FT VARIANT 93 93 R -> W (in Cemenelum; O(2) affinity up).
FT /FTId=VAR_020775.
FT VARIANT 95 95 D -> A (in Bassett; markedly reduced
FT oxygen affinity).
FT /FTId=VAR_025389.
FT VARIANT 95 95 D -> Y (in Setif; unstable).
FT /FTId=VAR_002814.
FT VARIANT 96 96 P -> A (in Denmark Hill; O(2) affinity
FT up).
FT /FTId=VAR_002815.
FT VARIANT 96 96 P -> T (in Godavari; O(2) affinity up).
FT /FTId=VAR_002816.
FT VARIANT 98 98 N -> K (in Dallas; O(2) affinity up).
FT /FTId=VAR_002817.
FT VARIANT 100 100 K -> E (in Turriff).
FT /FTId=VAR_002818.
FT VARIANT 103 103 S -> R (in Manitoba; slightly unstable;
FT dbSNP:rs41344646).
FT /FTId=VAR_002819.
FT VARIANT 104 104 H -> R (in Contaldo; unstable).
FT /FTId=VAR_002820.
FT VARIANT 104 104 H -> Y (in Charolles).
FT /FTId=VAR_025390.
FT VARIANT 110 110 L -> R (in Suan-Dok; unstable; causes
FT alpha-thalassemia).
FT /FTId=VAR_002821.
FT VARIANT 111 111 A -> D (in Petah Tikva; unstable; causes
FT alpha-thalassemia).
FT /FTId=VAR_002822.
FT VARIANT 113 113 H -> D (in Hopkins-II; unstable).
FT /FTId=VAR_002823.
FT VARIANT 114 114 L -> H (in Twin Peaks).
FT /FTId=VAR_002824.
FT VARIANT 115 115 P -> L (in Nouakchott).
FT /FTId=VAR_002825.
FT VARIANT 115 115 P -> R (in Chiapas).
FT /FTId=VAR_002826.
FT VARIANT 115 115 P -> S (in Melusine).
FT /FTId=VAR_002827.
FT VARIANT 116 116 A -> D (in J-Tongariki).
FT /FTId=VAR_002828.
FT VARIANT 117 117 E -> A (in Ube-4).
FT /FTId=VAR_002829.
FT VARIANT 117 117 E -> EHLPAE (in Zaire).
FT /FTId=VAR_002830.
FT VARIANT 118 118 F -> FI (in Phnom Penh).
FT /FTId=VAR_002831.
FT VARIANT 119 119 T -> TEFT (in Grady).
FT /FTId=VAR_002832.
FT VARIANT 121 121 A -> E (in J-Meerut/J-Birmingham).
FT /FTId=VAR_002833.
FT VARIANT 122 122 V -> M (in Owari).
FT /FTId=VAR_002834.
FT VARIANT 123 123 H -> Q (in Westmead).
FT /FTId=VAR_002835.
FT VARIANT 126 126 L -> P (in Quong Sze; causes alpha-
FT thalassemia).
FT /FTId=VAR_002836.
FT VARIANT 126 126 L -> R (in Plasencia; family with
FT moderate microcytosis and hypochromia).
FT /FTId=VAR_025391.
FT VARIANT 127 127 D -> G (in West One).
FT /FTId=VAR_025392.
FT VARIANT 127 127 D -> V (in Fukutomi; O(2) affinity up).
FT /FTId=VAR_002837.
FT VARIANT 127 127 D -> Y (in Monteriore; O(2) affinity up).
FT /FTId=VAR_002838.
FT VARIANT 128 128 K -> N (in Jackson).
FT /FTId=VAR_002839.
FT VARIANT 130 130 L -> P (in Tunis-Bizerte; unstable;
FT causes alpha-thalassemia).
FT /FTId=VAR_002840.
FT VARIANT 131 131 A -> D (in Yuda; O(2) affinity down).
FT /FTId=VAR_002842.
FT VARIANT 131 131 A -> P (in Sun Prairie; unstable).
FT /FTId=VAR_002841.
FT VARIANT 132 132 S -> P (in Questembert; highly unstable;
FT causes alpha-thalassemia).
FT /FTId=VAR_002843.
FT VARIANT 134 134 S -> R (in Val de Marne; O(2) affinity
FT up).
FT /FTId=VAR_002844.
FT VARIANT 136 136 V -> E (in Pavie).
FT /FTId=VAR_002845.
FT VARIANT 137 137 L -> M (in Chicago).
FT /FTId=VAR_002846.
FT VARIANT 137 137 L -> P (in Bibba; unstable; causes alpha-
FT thalassemia).
FT /FTId=VAR_002847.
FT VARIANT 137 137 L -> R (in Toyama).
FT /FTId=VAR_035242.
FT VARIANT 139 139 S -> P (in Attleboro; O(2) affinity up).
FT /FTId=VAR_002848.
FT VARIANT 140 140 K -> E (in Hanamaki; O(2) affinity up).
FT /FTId=VAR_002849.
FT VARIANT 140 140 K -> T (in Tokoname; O(2) affinity up).
FT /FTId=VAR_002850.
FT VARIANT 141 141 Y -> H (in Rouen/Ethiopia; O(2) affinity
FT up).
FT /FTId=VAR_002851.
FT VARIANT 142 142 R -> C (in Nunobiki; O(2) affinity up).
FT /FTId=VAR_002852.
FT VARIANT 142 142 R -> H (in Suresnes; O(2) affinity up).
FT /FTId=VAR_002854.
FT VARIANT 142 142 R -> L (in Legnano; O(2) affinity up).
FT /FTId=VAR_002853.
FT VARIANT 142 142 R -> P (in Singapore).
FT /FTId=VAR_002855.
FT CONFLICT 10 10 N -> H (in Ref. 13; BAD97112).
FT HELIX 5 18
FT HELIX 19 21
FT HELIX 22 36
FT HELIX 38 43
FT STRAND 45 47
FT STRAND 50 52
FT HELIX 54 72
FT TURN 73 75
FT HELIX 77 80
FT HELIX 82 90
FT TURN 91 93
FT HELIX 97 113
FT TURN 115 117
FT HELIX 120 138
FT HELIX 139 141
SQ SEQUENCE 142 AA; 15258 MW; 15E13666573BBBAE CRC64;
MVLSPADKTN VKAAWGKVGA HAGEYGAEAL ERMFLSFPTT KTYFPHFDLS HGSAQVKGHG
KKVADALTNA VAHVDDMPNA LSALSDLHAH KLRVDPVNFK LLSHCLLVTL AAHLPAEFTP
AVHASLDKFL ASVSTVLTSK YR
//

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 141800
*RECORD*
*FIELD* NO
141800
*FIELD* TI
+141800 HEMOGLOBIN--ALPHA LOCUS 1; HBA1
;;3-PRIME @ALPHA-GLOBIN GENE;;
MINOR ALPHA-GLOBIN LOCUS
read moreMETHEMOGLOBINEMIA, ALPHA-GLOBIN TYPE, INCLUDED;;
ERYTHREMIA, ALPHA-GLOBIN TYPE, INCLUDED
*FIELD* TX

DESCRIPTION

The alpha and beta loci determine the structure of the 2 types of
polypeptide chains in the tetrameric adult hemoglobin, Hb A,
alpha-2/beta-2. The alpha locus also determines a polypeptide chain, the
alpha chain, in fetal hemoglobin (alpha-2/gamma-2), in hemoglobin
A2(alpha-2/delta-2), and in embryonic hemoglobin (alpha-2/epsilon-2).
The number of normal alpha genes (3, 2, 1 or none) in Asian cases of
alpha-thalassemia (604131) results in 4 different alpha-thalassemia
syndromes (Kan et al., 1976). Three normal alpha genes gives a silent
carrier state. Two normal alpha genes results in microcytosis (so-called
heterozygous alpha-thalassemia). One normal alpha gene results in
microcytosis and hemolysis (so-called Hb H disease, 613978). No normal
alpha gene results in 'homozygous alpha-thalassemia' manifested as fatal
hydrops fetalis.

MAPPING

By studies of somatic cell hybrids, Deisseroth et al. (1976) showed that
the alpha and beta loci are on different chromosomes.

Deisseroth et al. (1977) combined the methods of somatic cell
hybridization and DNA-cDNA hybridization to establish assignment of the
alpha-globin locus to chromosome 16. This represents an extension of the
cell hybridization method permitting mapping of genes that are not
functional in the cultured cell. Deisseroth and Hendrick (1978)
confirmed the assignment of the alpha locus to chromosome 16 by means of
cotransfer of this gene with the human APRT gene, known to be on 16 (see
102600), into mouse erythroleukemia cells. (The APRT gene is on the long
arm of chromosome 16.)

Weitkamp et al. (1977) presented data concerning linkage of the alpha
and beta loci to 34 marker loci. Data on alpha-thalassemia, combined
with those on the Hopkins-2 variant, excluded linkage of alpha and
haptoglobin (140100) at a recombination fraction less than 0.15.

On the basis of findings in a case of partial trisomy 16, Wainscoat et
al. (1981) concluded that the alpha-globin genes are on segment
16pter-p12. By combining somatic cell hybridization with a cDNA probe in
the study of a cell line with reciprocal translocation between 16q and
11q, Koeffler et al. (1981) showed that the alpha-globin genes are on
the short arm of 16. Gerhard et al. (1981) used an improved method of in
situ hybridization to confirm the assignment of the alpha-globin cluster
to chromosome 16p. The evidence on the precise location of HBAC was
conflicting, with assignments from 16p13.33 to 16p13.11 (Reeders, 1986).
The fact that adult polycystic kidney disease (APKD; 173900) is proximal
to HBAC and is on the 5-prime side of HBAC appeared to indicate that the
order is 16cen--APKD--5-prime HBZ1--HBA1--3-prime HVR--pter. (3-prime
HVR is the hypervariable region used in mapping APKD to 16p.)

On the basis of the findings in a fetus with an unbalanced translocation
involving 16p, Breuning et al. (1987) concluded that the HBA cluster is
distal to PGP (172280).

By a combination of in situ hybridization, Southern blot analysis, and
linkage analysis using the fragile site 16p12.3 and translocation
breakpoints within band 16p13.1, Simmers et al. (1987) mapped the
alpha-globin gene complex to 16pter-p13.2.

CYTOGENETICS

Buckle et al. (1988) described a child in whom cytogenetic analysis
indicated monosomy for 16pter-p13.3. DNA studies showed that the patient
had not inherited either maternal alpha-globin allele. The child had the
alpha-thalassemia trait as well as moderate mental retardation and
dysmorphic features. They determined that the gene is located in the
16pter-p13.3 segment. After reviewing earlier data placing the
alpha-globin cluster slightly more proximal, they concluded that the
findings in this child may be more reliable.

GENE STRUCTURE

Orkin (1978) identified alpha-globin gene fragments in restriction
endonuclease digests of total DNA after electrophoresis by hybridization
with P32-labeled cDNA probes. The data indicated that the alpha genes
occur in duplicate and that the 2 copies lie close together. Thus direct
physical evidence was provided for the duplication deduced from the
findings with mutant alpha chains and with the alpha-thalassemias and
the kinetics of hybridization in solution. The 2 alpha chains lie about
3.7 kilobases apart.

Leder et al. (1978) presented evidence that the alpha and beta genes of
all adult mammalian hemoglobins have 2 intervening sequences at
analogous positions.

GENE FUNCTION

Straub et al. (2012) reported a model for the regulation of nitric oxide
(NO) signaling by demonstrating that hemoglobin alpha, encoded by the
HBA1 and HBA2 (141850) genes, is expressed in human and mouse arterial
endothelial cells and enriched at the myoendothelial junction, where it
regulates the effects of NO on vascular reactivity. Notably, this
function is unique to hemoglobin alpha and is abrogated by its genetic
depletion. Mechanistically, endothelial hemoglobin alpha heme iron in
the Fe(3+) state permits NO signaling, and this signaling is shut off
when hemoglobin alpha is reduced to the Fe(2+) state by endothelial
cytochrome b5 reductase 3 (CYB5R3; 613213). Genetic and pharmacologic
inhibition of CYB5R3 increased NO bioactivity in small arteries. Straub
et al. (2012) concluded that their data revealed a mechanism by which
the regulation of the intracellular hemoglobin alpha oxidation state
controls nitric oxide synthase (NOS; see 163729) signaling in
nonerythroid cells. The authors suggested that this model may be
relevant to heme-containing globins in a broad range of NOS-containing
somatic cells.

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

Wilson et al. (1977) described a possible nucleotide polymorphism in the
untranslated 3-prime region of the alpha-globin gene and suggested that
the heterogeneity is related to the existence of 2 alpha gene loci.

Musumeci et al. (1978) pointed out that the combination of
alpha-thalassemia and beta-thalassemia leads to less severe clinical
expression of homozygous beta-thalassemia. The rarity of a chromosome 16
with both alpha loci deleted (as demonstrated by the restriction
endonuclease mapping technique of Southern) explains the rarity of
severe forms of alpha-thalassemia in Africans, e.g., Hb H disease, which
requires loss of 3 alpha loci and homozygous alpha-thalassemia which
requires loss of 4 alpha loci (Dozy et al., 1979).

By restriction endonuclease mapping, Goossens et al. (1980) identified
12 persons heterozygous for a chromosome carrying 3 alpha genes. There
were no hematologic abnormalities. The frequency was 0.0036 in American
Blacks and 0.05 in Greek Cypriots. They had previously shown a frequency
of 0.16 for the single alpha-globin locus in black Americans. The single
locus had a frequency of 0.18 in Sardinians, but none of 125 Sardinians
had a triple alpha locus, suggesting that the former had a selective
advantage. Greek Cypriots have a frequency of 0.07 for the single alpha
locus. Among 645 Japanese subjects studied, Nakashima et al. (1990)
found 10 persons heterozygous for a chromosome with the triplicated
alpha-globin locus. Thus, the frequency of the triplicate alpha locus
was 0.008 in this population, while that of the single alpha-locus,
i.e., the alpha-thalassemia-2 gene, may be lower than 0.0008. Analysis
of haplotypes suggested that the triple alpha loci may have had multiple
origins. Nakashima et al. (1990) commented on the fact that in Melanesia
the frequency of the triplicated genotype is about the same (Flint et
al., 1986) as in Japan, whereas the frequency of the single alpha gene
is much higher, compatible with a selective advantage vis-a-vis malaria.
Liebhaber et al. (1981) found identity of the alpha-1-globin genes from
an Asian and a Caucasian. Furthermore, the alpha-1 and alpha-2 genes
have a much higher degree of homology than would be predicted from the
timing of the duplication before the bird-mammal divergence (about 300
Myr ago). Liebhaber et al. (1981) presented this as evidence for the
existence of mechanisms for suppression of allelic polymorphisms and for
exchange of genetic information within the alpha-globin gene complex.
See 142200 for a discussion of gene conversion in relation to a
comparably surprising homology of the 2 gamma-globin genes.

Lehmann and Carrell (1984) suggested the use of the following
nomenclature for alpha-thalassemias based on the number of alpha-globin
genes that are missing or abnormal: 1-alpha-thalassemia (silent type);
2-alpha-thalassemia, trans or cis (thalassemia trait);
3-alpha-thalassemia (Hb H disease); and 4-alpha-thalassemia (Hb Bart's
hydrops fetalis). In this scheme, homozygous Hb Constant Spring is a
2-alpha-thalassemia which, if combined with a cis 2-alpha-thalassemia
heterozygous Hb Constant Spring, gives a 3-alpha-thalassemia and results
in Hb H disease. Lehmann and Carrell (1984) also proposed that the 2
alpha-globin genes be designated as 5-prime (now alpha-2) and 3-prime
(now alpha-1). Liebhaber and Cash (1985) described a method for
identifying whether the alpha-1 or alpha-2 locus is the site of
particular alpha-globin mutations. Rubin and Kan (1985) described a
sensitive method for determining how many alpha-globin genes are
present. It had the advantages of not requiring restriction enzyme
digestion and gel electrophoresis and using the much more stable isotope
(35)S rather than 32(P) for labeling. Only a small sample of DNA is
needed. Application of the approach to diagnosis of Down syndrome was
proposed. Assum et al. (1985) added a fourth restriction site
polymorphism in the alpha-globin gene cluster. Compared to the
beta-globin cluster, the alpha-globin cluster seemed to show a poverty
of DNA polymorphism; however, Higgs et al. (1986) demonstrated a
remarkable degree of DNA polymorphism in the alpha-globin gene cluster.
In addition, the RFLP haplotype is associated with hypervariable regions
of DNA.

Pseudo-alpha-1 (HBAP1), a pseudogene, is defective in several respects,
including splice junction mutations and premature termination codons.
Hardison et al. (1986) identified a previously undetected pseudogene in
the alpha-globin cluster. It was not detected by hybridization studies
but was found only on sequence analysis. Hardison et al. (1986)
suggested that 'divergent copies of a large number of genes may comprise
a substantial fraction of the slowly renaturing DNA of mammalian
genomes.' The newly detected pseudogene, which will be symbolized HBAP2,
is only 65 bp 3-prime to the polyadenylation site of zeta-1 (HBZP). The
sequence is: 5-prime--HBZ--HBZP--HBAP2--HBA2--HBA1--3-prime. (The
functional Hba gene of the mouse is on chromosome 11, but pseudogenes
are dispersed to other chromosomes (e.g., Hba-ps3 to mouse chromosome
15) (Popp et al., 1981; Leder et al., 1981; Eicher and Lee, 1991).)

Vandenplas et al. (1987) described a new form of alpha-0 thalassemia in
a South African family ascertained through a case of Hb H disease. A
novel deletion of 22.8-23.7 kb of DNA removed 3 pseudogenes as well as
the alpha-2 and alpha-1 genes. Since the alpha-2-globin gene encodes the
majority of alpha-globin, a thalassemic mutation of the alpha-1-globin
gene would be expected to result in a less severe loss of alpha-chain
synthesis.

Moi et al. (1987) described an initiation codon mutation, AUG-to-GUG, in
the alpha-1-globin gene. As predicted, the degree of interference with
alpha-globin synthesis was less in this mutation than in the mutation in
the initiation codon of the alpha-2-globin gene (see 141850).

Hill et al. (1987) described a unique nondeletion form of Hb H disease
in Papua New Guinea: all 4 alpha genes were intact. Hill et al. (1987)
commented on the striking difference in the hemoglobinopathies that
occur in Southeast Asia and in Melanesia. In the former area, Hb E, Hb
Constant Spring, and the Southeast Asian form of deletion
alpha-0-thalassemia are all common, whereas these forms have never been
found in Melanesians or Polynesians.

Jarman and Higgs (1988) identified a highly polymorphic region
approximately 100 kb upstream of the alpha-globin genes and referred to
it as 5-prime HVR. This is a valuable genetic marker for 16p. Higgs et
al. (1989) gave a comprehensive review of the molecular genetics of the
alpha-globin gene cluster, including its diseases.

Hatton et al. (1990) presented evidence for the existence of an
alpha-locus control region (LCRA; 152422). This would be comparable to
the beta-LCR which controls expression of the beta-like genes; see
152424. Liebhaber et al. (1990) identified an individual with
alpha-thalassemia in whom structurally normal alpha-globin genes were
inactivated in cis by a discrete de novo 35-kb deletion located about 30
kb 5-prime to the alpha-globin gene cluster. They concluded that the
deletion inactivates expression of the alpha-globin genes by removing
one or more of the previously identified upstream regulatory sequences
that are critical to expression of the alpha-globin genes.

Hemoglobinopathies of alpha-globin can result from missense mutations at
either of the 2 alpha-globin loci, HBA1 or HBA2. Since the normal HBA1
and HBA2 genes encode an identical alpha globin, these mutants cannot be
assigned to their specific loci on the basis of protein structural
analysis. A clue to the encoding locus, HBA1 versus HBA2, is provided by
the relative concentration of the alpha-globin mutant in the erythrocyte
based on the 2- to 3-fold higher level of expression of the HBA2 gene
(Liebhaber et al., 1986). However, since variables such as protein
stability, efficiency of hemoglobin tetramer formation, and other
factors can affect the steady-state levels of globin mutants, a
definitive locus assignment must be directly determined. Cash et al.
(1989) quantitated the expression of 2 alpha-globin structural mutants
found in the Caribbean basin, Fort de France and Spanish Town, and
showed that they are HBA1 and HBA2 mutants, respectively, on the basis
of low or high expression.

Wilkie et al. (1991) described major polymorphic length variation in the
terminal region of 16p (16p13.3) by physically linking the alpha-globin
locus with probes to telomere-associated repeats. They found 3 alleles
in which the alpha-globin genes lie 170 kb, 350 kb, or 430 kb from the
telomere. The 2 most common alleles were found to contain different
terminal segments, starting 145 kb distal to the alpha-globin genes.
Beyond this boundary these alleles are nonhomologous, yet each contains
sequences related to other, different chromosome termini. This
chromosome-size polymorphism probably arose by occasional exchanges
between the subtelomeric regions of nonhomologous chromosomes. Wilkie et
al. (1991) raised the possibility that the high frequency of trisomy 16
may be related to this nonhomology of the 2 common 16pter alleles in
their subtelomeric region.

Huisman et al. (1996) found that of the 141 codons of the alpha-globin
genes (there are no sequence differences between the coding regions of
the alpha-2 and alpha-1 genes), as many as 99 have been found to be
mutated; for several, 3 or 4 mutations have been discovered, while 5
mutations are known for codons 23, 75, and 94, and 6 for codon 141. The
mutations appear to occur at random; thus, either one of the 3 bases are
replaced in the 199 known alpha-globin gene mutants.

The suggestion that alpha(+)-thalassemia has achieved a high frequency
in some populations as a result of selection by malaria is based on a
number of epidemiologic studies. In the southwest Pacific region, there
is a striking geographic correlation between the frequency of
alpha(+)-thalassemia and the endemicity of Plasmodium falciparum. Allen
et al. (1997) undertook a prospective case-control study of children
with severe malaria on the north coast of Papua New Guinea, where
malaria transmission is intense and alpha(+)-thalassemia affects more
than 90% of the population (homozygotes comprise approximately 55% and
heterozygotes 37% of the population). Compared with normal children, the
risk of having severe malaria was 0.40 in alpha(+)-thalassemia
homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of
hospital admission with infections other than malaria also was reduced
to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This
clinical study demonstrated that a malaria resistance gene protects
against disease caused by infections other than malaria. A reduction in
mortality greater than that attributable directly to malaria had been
observed after the prevention of malaria by insecticides,
chemoprophylaxis, and insecticide-impregnated bed nets. Previous
observations that direct malaria mortality cannot account for observed
hemoglobin S gene frequencies suggest that the findings of this study
may apply equally to other malaria resistance genes.

Fung et al. (1999) reported 3 cases of homozygous alpha-thalassemia who
survived beyond the newborn period, all with hypospadias. Review of the
literature identified 2 additional cases. Fung et al. (1999) suggested
that the hypospadias may have been secondary to the in utero edema
leading to failure of fusion of urogenital folds or due to defect or
deletion of another gene at 16p13.3.

For a review of hydrops fetalis caused by alpha-thalassemia, see Chui
and Waye (1998).

From work on the mouse model of alpha-thalassemia, Leder et al. (1999)
demonstrated that a normal beta-globin allele can act as a modifying
gene ameliorating the severity of alpha-thalassemia. They found that the
phenotype of alpha-thalassemia was strongly influenced by the genetic
background in which the mutation resided; when both mutant genes were on
a chromosome derived from strain 129, the phenotype was severe, whereas
it was mild when the gene was on a 129 chromosome and a C57BL/6
chromosome. Linkage mapping indicated that the modifying gene is very
tightly linked to the beta-globin locus (lod score = 13.3). Furthermore,
the severity of the phenotype correlated with the size of
beta-globin-containing inclusion bodies, which accumulate in red blood
cells and likely accelerate their destruction. The beta-major globin
chains encoded by the 2 strains differed by 3 amino acids, one of which
is a glycine-to-cysteine substitution at position 13. The cys13 should
be available for interchain disulfide bridging and consequent
aggregation between excess beta chains. This normal polymorphic
variation between murine beta-globin chains could account for the
modifying action of the unlinked beta-globin locus. Here, the variation
in severity of the phenotype would not depend on a change in the ratio
between alpha and beta chains but on the chemical nature of the normal
beta chain, which is in excess. This work also indicated that modifying
genes can be normal variants that, absent an apparent physiologic
rationale, may be difficult to identify on the basis of structure alone.

De Gobbi et al. (2006) identified a pathogenetic mechanism underlying a
variant form of the inherited blood disorder alpha-thalassemia.
Association studies of affected individuals from Melanesia localized the
disease trait to the telomeric region of human chromosome 16, which
includes the alpha-globin gene cluster, but no molecular defects were
detected by conventional approaches. After resequencing and using a
combination of chromatin immunoprecipitation and expression analysis on
a tiled oligonucleotide array, De Gobbi et al. (2006) identified a
gain-of-function regulatory single-nucleotide polymorphism (rSNP)
(141800.0218) in a nongenic region between the alpha-globin genes and
their upstream regulatory elements. The rSNP creates a new promoter-like
element that interferes with normal activation of all downstream
alpha-like globin genes. De Gobbi et al. (2006) concluded that their
work illustrates a strategy for distinguishing between neutral and
functionally important rSNPs, and it also identifies a pathogenetic
mechanism that could potentially underlie other genetic diseases.

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 that 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.

N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2
is involved have arbitrarily been included in this entry. Carver and
Kutlar (1995) listed 191 alpha-globin variants as of January 1995. The
syllabus by Huisman et al. (1996) listed 199 alpha-chain hemoglobin
variants as of January 1996. These included single-base mutations in the
alpha-2 and alpha-1 genes as well as 2-base mutations. Not included in
their syllabus were deletions in mutations that result in
alpha-thalassemia, even if such a change (point mutation or frameshift)
occurred in one of the coding regions of the gene. Information about the
alpha-thalassemias was provided by Higgs et al. (1989).

HISTORY

Gandini et al. (1977) concluded, incorrectly as it turned out, that the
alpha loci are on the long arm of chromosome 4 (4q28-q34). The
conclusion was based on a finding of excessive synthesis of alpha chains
in patients with duplication of this region.

*FIELD* AV
.0001
HEMOGLOBIN AICHI
HBA1, HIS50ARG

See Harano et al. (1984) and Baudin et al. (1987).

.0002
HEMOGLOBIN ALBANY-GEORGIA
HEMOGLOBIN ALBANY-SUMA
HBA1, LYS11ASN

This was found in a clinically normal black female in Albany, Georgia
(Webber et al., 1983). See also Shimasaki et al. (1983).

.0003
HEMOGLOBIN ANANTHARAJ
HBA1, LYS11GLU

See Pootrakul et al. (1975).

.0004
HEMOGLOBIN ANN ARBOR
HBA1, LEU80ARG

See Adams et al. (1972) and Adams (1974).

.0005
HEMOGLOBIN ARYA
HBA1, ASP47ASN

See Rahbar et al. (1975).

.0006
HEMOGLOBIN ATAGO
HBA1, ASP85TYR

See Fujiwara (1970) and Fujiwara et al. (1971).

.0007
HEMOGLOBIN ATTLEBORO
HBA1, SER138PRO

See McDonald et al. (1990).

.0008
HEMOGLOBIN AZTEC
HBA1, MET76THR

See Shelton et al. (1985).

.0009
HEMOGLOBIN BARI
HBA1, HIS45GLN

See Marinucci et al. (1980).

.0010
HEMOGLOBIN BEIJING
HBA1, LYS16ASN

See Liang et al. (1982).

.0011
HEMOGLOBIN BIBBA
HBA1, LEU136PRO

See Kleihauer et al. (1968). (This is actually an allelic variant of the
HBA2 gene; see 141850.0030.)

.0012
HEMOGLOBIN BOURMEDES
HBA1, PRO37ARG

See Dahmane-Arbane et al. (1987).

.0014
HEMOGLOBIN BROUSSAIS
HEMOGLOBIN J (BROUSSAIS);;
HEMOGLOBIN TAGAWA I
HBA1, LYS90ASN

See de Traverse et al. (1966), Yanase et al. (1968), Vella et al.
(1970), and Fleming et al. (1978).

.0015
HEMOGLOBIN CATONSVILLE
HBA1, INS GLU, PRO37/GLU/THR38

See Virshup et al. (1988). Moo-Penn et al. (1989) identified insertion
of a glutamic acid residue between proline-37 and threonine-38 in an
unstable hemoglobin variant. The PCR-amplified fragment of the variant
gene showed insertion of a GAA codon. In the normal alpha-globin gene
cluster, GAG is the codon for glutamic acid. Moo-Penn et al. (1989)
suggested that this mutation may have resulted from nonhomologous
nonallelic gene conversion.

.0016
HEMOGLOBIN CHAD
HBA1, GLU23LYS

See Boyer et al. (1968).

.0017
HEMOGLOBIN CHAPEL HILL
HBA1, ASP74GLY

See Orringer et al. (1976).

.0018
HEMOGLOBIN CHESAPEAKE
HBA1, ARG92LEU

See Clegg et al. (1966) and Harano et al. (1983). Polycythemia is the
only clinical feature. This was the first polycythemia-producing variant
to be described (Charache et al., 1966).

.0019
HEMOGLOBIN CHIAPAS
HBA1, PRO114ARG

See Jones et al. (1968).

.0020
HEMOGLOBIN CHICAGO
HBA1, LEU136MET

See Bowman et al. (1986).

.0021
HEMOGLOBIN CHONGQING
HBA1, LEU2ARG

See Zeng et al. (1984).

.0022
HEMOGLOBIN CONTALDO
HBA1, HIS103ARG

Unstable hemoglobin due to disruption of hydrogen bond between alpha 103
(his) and beta 108 (asn) (Sciarratta et al., 1984).

.0023
HEMOGLOBIN CORDELE
HBA1, ASP47ALA

See Nakatsuji et al. (1984).

.0024
HEMOGLOBIN DAGESTAN
HBA1, LYS60GLU

See Spivak et al. (1981) and Lacombe et al. (1987).

.0025
HEMOGLOBIN DALLAS
HBA1, ASN97LYS

See Dysert et al. (1982).

.0026
HEMOGLOBIN DANESHGAH-TEHRAN
HBA1, HIS72ARG

See Rahbar et al. (1973) and de Weinstein et al. (1985).

.0027
HEMOGLOBIN DENMARK HILL
HBA1, PRO95ALA

See Wiltshire et al. (1972).

.0028
HEMOGLOBIN DUAN
HBA1, ASP75ALA

See Liang et al. (1981, 1988).

.0029
HEMOGLOBIN DUNN
HBA1, ASP6ASN

See Jue et al. (1979) and Baklouti et al. (1988).

.0030
HEMOGLOBIN ETOBICOKE
HBA1, SER84ARG

See Crookston et al. (1969) and Headlee et al. (1983).

.0031
HEMOGLOBIN EVANSTON
HBA1, TRP14ARG

Honig et al. (1982) first described Hb Evanston in 2 black families. See
also Moo-Penn et al. (1983).

Harteveld et al. (2004) found this rare variant alone and in the
presence of common alpha-thalassemia deletions in 3 independent Asian
cases.

.0032
HEMOGLOBIN FERNDOWN
HBA1, ASP6VAL

See Lee-Potter et al. (1981).

.0033
HEMOGLOBIN FONTAINEBLEAU
HBA1, ALA21PRO

Wajcman et al. (1989) found this substitution in an Italian family. The
substitution produced no change in the stability or oxygen binding
properties of the hemoglobin molecule. The electrophoretic properties
were, furthermore, identical to those of Hb A, with the exception of
isoelectric focusing in which the variant migrated like Hb A1c. Hb
J(Nyanza), another substitution at position alpha-21, likewise causes no
hematologic disorder.

.0034
HEMOGLOBIN FORT DE FRANCE
HBA1, HIS45ARG

See Braconnier et al. (1977). Cash et al. (1989) confirmed that this is
a mutant of the HBA1 gene.

.0035
HEMOGLOBIN G (AUDHALI)
HBA1, GLU23VAL

See Marengo-Rowe et al. (1968).

.0037
HEMOGLOBIN G (FORT WORTH)
HEMOGLOBIN FORT WORTH
HBA1, GLU27GLY

This variant was described in 2 black families. Unusually low (5%)
concentration was found in heterozygotes, perhaps because of decreased
ability of the abnormal alpha chain to form dimers with beta chains. See
Schneider et al. (1971) and Carstairs et al. (1985).

.0038
HEMOGLOBIN G (GEORGIA)
HBA1, PRO95LEU

See Huisman et al. (1970).

.0039
MOVED TO 141850.0054
.0040
HEMOGLOBIN G (NORFOLK)
HBA1, ASP85ASN

See Cohen-Solal et al. (1975) and Lorkin et al. (1975).

.0041
HEMOGLOBIN G (PEST)
HBA1, ASP74ASN

Hb G (Pest) and Hb J (Buda) (141850.0008), both alpha-chain mutants,
occurred together in a Hungarian male with erythrocytosis. The
occurrence of some normal Hb A in this man showed the existence of at
least 2 alpha loci. See Brimhall et al. (1970, 1974) and Hollan et al.
(1972). Using polymerase chain reaction (PCR) to amplify selectively
alpha-1 and alpha-2-globin cDNAs, Mamalaki et al. (1990) then hybridized
the cDNAs to synthetic oligonucleotides specific for either the normal
or the mutated sequence. Using this approach, the alpha-globin
structural mutants J-Buda and G-Pest were found to be encoded by the
alpha-2 and the alpha-1-globin genes, respectively. The substitution in
G-Pest was a change from GAC to AAC at codon 74.

.0042
HEMOGLOBIN G (TAICHUNG)
HEMOGLOBIN Q;;
HEMOGLOBIN Q (THAILAND);;
HEMOGLOBIN MAHIDOL;;
HEMOGLOBIN ASABARA;;
HEMOGLOBIN KURASHIKI
HBA1, ASP74HIS

See Vella et al. (1958), Gammack et al. (1961), Lie-Injo et al. (1966,
1979); Blackwell and Liu (1970), Pootrakul and Dixon (1970), Lorkin et
al. (1970), Iuchi et al. (1978), and Higgs et al. (1980). Zeng et al.
(1992) demonstrated that the mutation is due to a GAC-to-CAC change in
codon 74 of the HBA1 gene. They developed a simple and accurate method
for diagnosis of the Hb Q (Thailand) variant based on restriction enzyme
analysis.

.0043
HEMOGLOBIN G (WAIMANALO)
HEMOGLOBIN AIDA
HBA1, ASP64ASN

See Blackwell et al. (1973) and Bunn et al. (1978). Schiliro et al.
(1991) found this variant in a Filipino mother and child living in
Sicily. They showed no hematologic abnormalities.

.0044
HEMOGLOBIN GARDEN STATE
HBA1, ALA82ASP

See Winter et al. (1978).

.0045
HEMOGLOBIN GRADY
HEMOGLOBIN DAKAR
HBA1, 3AA INS, 118THR-GLU-PHE119

At the time it was first studied by Huisman et al. (1974), hemoglobin
Grady was unique in having an insertion of threonine-glutamic
acid-phenylalanine between amino acids 118 and 119 of the alpha chain.
Several hemoglobins with deletions were then known (Leiden, Lyon,
Freiburg, Niteroi, Tochigi, St. Antoine, Tours and Gun Hill). Scott et
al. (1981) found no evidence of an extra (fifth) alpha gene. They
argued, therefore, that if, as supposed, Hb Grady arose by unequal
crossing over, the event occurred between alleles rather than between
the separate alpha-1 and alpha-2 loci. The glu-phe-thr insertion is a
repeat of normal residues 116, 117 and 118. See Cleek et al. (1983).
Substitution of glutamine for histidine at alpha 112 was thought to be
the change in hemoglobin Dakar; however, on restudy the hemoglobin was
found to be identical to Hb Grady (Garel et al., 1976).

.0046
HEMOGLOBIN GUANGZHOU
HEMOGLOBIN HANGZHOU
HBA1, ASP64GLY

See Jen and Liu (1987), Zhou et al. (1987), and Li et al. (1990).

.0047
HEMOGLOBIN GUIZHOU
HEMOGLOBIN UTSUNOMIYA
HBA1, PRO77ARG

See Hattori et al. (1985).

.0048
HEMOGLOBIN HANDA
HEMOGLOBIN MUNAKATA
HBA1, LYS90MET

See Harano et al. (1982) and Sugihara et al. (1983).

.0049
HEMOGLOBIN HANDSWORTH
HBA1, GLY18ARG

See Griffiths et al. (1977), Chih-chuan et al. (1981), and Al-Awamy et
al. (1985).

.0050
HEMOGLOBIN HARBIN
HBA1, LYS16MET

See Zeng et al. (1984).

.0051
HEMOGLOBIN HEKINAN
HBA1, GLU27ASP

See Harano et al. (1988). Using dot-blot analysis of amplified DNA with
(32)p-labeled probes, Zhao et al. (1990) located the mutation in codon
27 of the minor alpha-1 globin gene and showed that the change involved
a GAG (glutamic acid)-to-GAT (aspartic acid) mutation. Their patients
were 3 Chinese women from Macau.

In Thailand, Ngiwsara et al. (2004) described 2 unrelated cases of
compound heterozygosity for Hb Hekinan and alpha-thalassemia.

.0052
HEMOGLOBIN HIROSAKI
HBA1, PHE43LEU

See Ohba et al. (1975, 1978).

.0053
HEMOGLOBIN HOBART
HBA1, HIS20ARG

See Fleming et al. (1987).

.0054
HEMOGLOBIN HOPKINS 2
HBA1, HIS112ASP

Fast hemoglobin. See Smith and Torbert (1958), Itano and Robinson
(1960), Bradley et al. (1961), Ostertag et al. (1972), Clegg and
Charache (1978).

.0055
HEMOGLOBIN I
HEMOGLOBIN I (BURLINGTON);;
HEMOGLOBIN I (PHILADELPHIA);;
HEMOGLOBIN I (SKAMANIA);;
HEMOGLOBIN I (TEXAS)
HBA1, LYS16GLU

Fast hemoglobin. Substitution of aspartic acid for lysine at alpha 16
was first reported by Murayama (1962). However, Crick pointed out that
this substitution could not be accomplished by change in one base.
Restudy by Beale and Lehmann (1965) and by Schneider et al. (1966)
showed substitution of glutamic acid for lysine. Hemoglobin I was
thought to show sickling but this has been shown to be due to faulty
technique (Schneider et al., 1967). See Rucknagel et al. (1955),
Schwartz et al. (1957), Itano and Robinson (1959, 1960), Ranney et al.
(1962), O'Brien et al. (1964), Thompson et al. (1965), Schneider et al.
(1966), Bowman and Barnett (1967), Baur (1968), Labossiere and Vella
(1971), Fleming et al. (1978), and Liebhaber et al. (1984). The
hemoglobin I mutation is curious in that the mutation is present in HBA2
(141850.0011) as well as in HBA1.

.0057
HEMOGLOBIN IWATA
HBA1, HIS87ARG

See Shibata et al. (1980) and Liu et al. (1983).

.0058
HEMOGLOBIN J (ABIDJAN)
HBA1, GLY51ASP

See Cabannes et al. (1972).

.0059
HEMOGLOBIN J (ANATOLIA)
HBA1, LYS61THR

See Giordano et al. (1990).

.0060
HEMOGLOBIN J (BIRMINGHAM)
HEMOGLOBIN J (MEERUT)
HBA1, ALA120GLU

See Kamuzora and Lehmann (1974) and Blackwell et al. (1974).

.0062
HEMOGLOBIN J (CAMAGUEY)
HBA1, ARG141GLY

See Martinez et al. (1978). Romero et al. (1995) found this hemoglobin
variant in 3 Spanish families. The original description by Martinez et
al. (1978) was in a Cuban family of Spanish ancestry.

.0063
HEMOGLOBIN J (CAPE TOWN)
HBA1, ARG92GLN

See Botha et al. (1966), Harano et al. (1983), and Lambridis et al.
(1986).

.0064
HEMOGLOBIN J (CUBUJUQUI)
HBA1, ARG141SER

See Saenz et al. (1977) and Moo-Penn et al. (1981).

.0065
HEMOGLOBIN J (HABANA)
HBA1, ALA71GLU

See Colombo et al. (1974) and Ohba et al. (1983).

.0066
HEMOGLOBIN J (KUROSH)
HBA1, ALA19ASP

See Rahbar et al. (1976).

.0067
HEMOGLOBIN J (MEDELLIN)
HBA1, GLY22ASP

See Gottlieb et al. (1964).

.0068
HEMOGLOBIN J (NYANZA)
HBA1, ALA21ASP

See Kendall et al. (1973).

.0070
HEMOGLOBIN J (PARIS 1)
HEMOGLOBIN J (ALJEZUR)
HBA1, ALA12ASP

See Rosa et al. (1966), Trincao et al. (1968), and Marinucci et al.
(1979).

.0071
HEMOGLOBIN J (RAJAPPEN)
HBA1, LYS90THR

See Hyde et al. (1971).

.0072
HEMOGLOBIN J (ROVIGO)
HBA1, ALA53ASP

See Alberti et al. (1974) and Moo-Penn et al. (1978).

.0074
HEMOGLOBIN J (SINGA)
HBA1, ASN78ASP

See Wong et al. (1984).

.0075
HEMOGLOBIN J (SINGAPORE)
HBA1, ASN78ASP AND ALA79GLY

Since no simple frameshift mechanism could be imagined, the possibility
of 2 separate mutations was favored by Blackwell et al. (1972), who
suggested that 2 separate hemoglobins, appropriately called Hb J (Singa)
and Hb J (Pore), will be discovered eventually. Double mutation on the
same chromosome would seem more likely than crossing-over in a compound
heterozygote since the 2 codons involved are contiguous.

.0076
HEMOGLOBIN J (TASHIKUERGAN)
HBA1, ALA19GLU

See Houjun et al. (1984). Li et al. (1990) found this variant in
populations in the Silk Road region of China.

.0077
HEMOGLOBIN J (TONGARIKI)
HBA1, ALA115ASP

See Gajdusek et al. (1967) and Beaven et al. (1972). A homozygous
individual had only anomalous hemoglobin suggesting the existence of
only one alpha locus in Melanesians (Abramson et al., 1970).

.0078
HEMOGLOBIN J (TORONTO)
HBA1, ALA5ASP

See Crookston et al. (1965).

.0079
HEMOGLOBIN JACKSON
HBA1, LYS127ASN

See Moo-Penn et al. (1976).

.0080
HEMOGLOBIN KARACHI
HBA1, ALA5PRO

See Ahmad et al. (1986).

.0081
HEMOGLOBIN KARIYA
HBA1, LYS40GLU

See Harano et al. (1983) and Imai et al. (1989).

.0082
HEMOGLOBIN KAWACHI
HBA1, PRO44ARG

See Harano et al. (1982).

.0083
HEMOGLOBIN KOELLIKER
HEMOGLOBIN F (KOELLIKER)
HBA1, ARG141DEL

Not a genetic change. The C-terminal amino acid, 141, of the alpha chain
(arginine) is missing, probably from the action of a carboxypeptidase
present in normal plasma. This unusual fast hemoglobin is observed in
persons with hemolysis. The change can occur in fetal hemoglobin also
(Kohne et al., 1977). See Marti et al. (1967) and Schiliro et al.
(1982).

.0084
HEMOGLOBIN KOKURA
HEMOGLOBIN BEILINSON;;
HEMOGLOBIN MICHIGAN-I;;
HEMOGLOBIN MICHIGAN-II;;
HEMOGLOBIN L (GASLINI);;
HEMOGLOBIN TAGAWA II;;
HEMOGLOBIN UMI;;
HEMOGLOBIN MUGINO;;
HEMOGLOBIN YUKUHASHI-2
HBA1, ASP47GLY

See Yamaoka et al. (1960), Ooya et al. (1961), Sumida (1975), and Ohba
et al. (1982). The change is in TP IV (DeVries et al., 1963).

.0086
HEMOGLOBIN L (PERSIAN GULF)
HBA1, GLY57ARG

See Rahbar et al. (1969).

.0087
HEMOGLOBIN LEGNANO
HBA1, ARG141LEU

See Mavilio et al. (1978).

.0088
HEMOGLOBIN LE LAMENTIN
HBA1, HIS20GLN

See Sellaye et al. (1982), Harano et al. (1983), and Malcorra-Azpiazu et
al. (1988).

.0089
HEMOGLOBIN LILLE
HBA1, ASP74ALA

See Djoumessi et al. (1981) and Lu et al. (1984).

.0090
HEMOGLOBIN LOIRE
HBA1, ALA88SER

This variant was discovered in a 10-year-old Algerian boy born in Loire.
The child had erythrocytosis and microcytosis, the latter being due to
iron deficiency (Baklouti et al., 1988).

.0091
HEMOGLOBIN LUXEMBOURG
HBA1, TYR24HIS

Groff et al. (1989) found this substitution in association with mild
hemolytic anemia and increased indirect bilirubinemia in a family
originating from the Netherlands.

.0092
HEMOGLOBIN M (BOSTON)
HEMOGLOBIN GOTHENBURG;;
HEMOGLOBIN M (GOTHENBURG);;
HEMOGLOBIN M (OSAKA);;
HEMOGLOBIN M (KISKUNHALAS)
HBA1, HIS58TYR

The aberrant hemoglobins associated with methemoglobinemia are referred
to as hemoglobin M. Most of the hemoglobin M variants have substitutions
of histidine at alpha 58, alpha 87, beta 63, or beta 92. These 4 amino
acids are critical to the binding of the heme group. The exception is
hemoglobin M (Milwaukee-1). See Gerald et al. (1957), Hansen et al.
(1960), Gerald and Efron (1961), Betke (1962), Hayashi et al. (1964),
Shimizu et al. (1965), Suzuki et al. (1965), Hollan et al. (1967), and
Pulsinelli et al. (1973).

.0093
HEMOGLOBIN M (IWATE)
HEMOGLOBIN M (KANKAKEE);;
HEMOGLOBIN M (OLDENBURG);;
HEMOGLOBIN M (SENDAI)
HBA1, HIS87TYR

Hb Iwate was the first variant hemoglobin found in Japan (Shibata et
al., 1960). Familial cyanosis had been recognized for about 200 years in
the prefecture of Iwate in Honshu, where about 70 affected persons were
identified in the 1950s. It was called 'kuchikuro,' or 'blackmouth.' In
each form of methemoglobinemia, the heme iron is stabilized in the
ferric form. Patients with the Hb M alpha forms are cyanotic at birth;
those with the Hb M beta forms are usually not cyanotic until they are 3
months of age. Horst et al. (1987) showed that the Iwate mutation
involves the alpha-1 globin gene. Specifically, they demonstrated a
CAC-to-TAC mutation in codon 87 of that gene. They showed that the Iwate
mutation can be identified directly on RsaI digestion. See Meyering et
al. (1960), Shibata et al. (1961), Gerald and Efron (1961), Miyaji et
al. (1962), Heller (1962), Heller et al. (1962), Tonz et al. (1962),
Shibata (1964), Tamura (1964), Shimizu et al. (1965), Pik and Tonz
(1966), Maggio et al. (1981), and Mayne et al. (1986).

Ameri et al. (1999) likewise determined that the molecular defect in 2
patients with Hb M (Kankakee) was his87 to tyr in the HBA1 gene. The
proportion of Hb M (Kankakee) observed was higher than that predicted
for an alpha-1-globin variant. They presented evidence suggesting that
the greater-than-expected proportion of Hb M (Kankakee) results from
preferential association of the electronegative beta-globin chains with
the alpha-(M)-globin chains that are more electropositive than normal
alpha-globin chains.

.0094
MOVED TO 141850.0047
.0095
HEMOGLOBIN MATSUE-OKI
HBA1, ASP75ASN

See Ohba et al. (1977) and Yi-Tao et al. (1982).

.0096
HEMOGLOBIN MEMPHIS
HBA1, GLU23GLN

Substitution of glutamine for glutamic acid at alpha 23. A hemoglobin S
homozygote who also carries this abnormal hemoglobin has a mild form of
sickle cell anemia. See Kraus et al. (1965, 1967) and Cooper et al.
(1973).

.0097
HEMOGLOBIN MEXICO
HEMOGLOBIN J;;
HEMOGLOBIN J (MEXICO);;
HEMOGLOBIN J (PARIS 2);;
HEMOGLOBIN UPPSALA
HBA1, GLN54GLU

Fast hemoglobin. See Jones et al. (1963, 1968), Beckman et al. (1966),
Labie and Rosa (1966), Quattrin and Ventruto (1967), Fessas et al.
(1969), and Trabuchet et al. (1982).

.0098
HEMOGLOBIN MILLEDGEVILLE
HBA1, PRO44LEU

See Honig et al. (1980).

.0099
HEMOGLOBIN MIYANO
HBA1, THR41SER

See Ohba et al. (1989).

.0100
HEMOGLOBIN MIZUSHI
HBA1, ASP75GLY

No hematologic abnormality. See Iuchi et al. (1980).

.0101
HEMOGLOBIN MOABIT
HBA1, LEU86ARG

See Knuth et al. (1979).

.0104
HEMOGLOBIN NECKER ENFANTS-MALADES
HBA1, HIS20TYR

This variant was detected by chromatography in the course of screening
diabetics for Hb A1c (Wajcman et al., 1980).

.0105
HEMOGLOBIN NIGERIA
HBA1, SER81CYS

See Honig et al. (1978).

.0106
HEMOGLOBIN NOKO
HBA1, MET76LYS

See Shibata et al. (1981).

.0107
HEMOGLOBIN NORFOLK
HEMOGLOBIN J (NORFOLK);;
HEMOGLOBIN KAGOSHIMA;;
HEMOGLOBIN NISHIK
HBA1, GLY57ASP

Fast hemoglobin. See Ager et al. (1958), Baglioni (1962), Huntsman et
al. (1963), Hanada et al. (1964), Imamura (1966), and Lehmann and
Carrell (1969).

.0108
HEMOGLOBIN NOUAKCHOTT
HBA1, PRO114LEU

See Wajcman et al. (1989).

.0109
HEMOGLOBIN NUNOBIKI
HBA1, ARG141CYS

This hemoglobin showed an extremely high oxygen affinity. The patient,
who had 'marginal erythrocytosis,' was shown to have 13.1% Hb Nunobiki
(Shimasaki, 1985).

.0110
HEMOGLOBIN O (INDONESIA)
HEMOGLOBIN O (BUGINESE-X);;
HEMOGLOBIN BUGINESE-X;;
HEMOGLOBIN O (OLIVIERE);;
HEMOGLOBIN OLIVIERE
HBA1, GLU116LYS

See Lie-Injo and Sadono (1958), Baglioni and Lehmann (1962), and Sansone
et al. (1970).

Daud et al. (2001) investigated the occurrence of hemoglobin O
(Indonesia) in related ethnic populations of the Indonesian archipelago.
Nineteen individuals heterozygous for this variant were identified in 4
ethnic populations. The level of Hb O (Indonesia) in 17 of the
individuals was 11.6 +/- 1.0%, significantly lower than the expected 17
to 22%, indicating the instability of Hb O (Indonesia).

.0111
HEMOGLOBIN O (PADOVA)
HBA1, GLU30LYS

See Vettore et al. (1974), Kilinc et al. (1985), and Martin et al.
(1990). Schnedl et al. (1997) showed that the silent hemoglobin O Padova
mutation causes an additional peak on high performance liquid
chromatography (HPLC) and falsely low HbA(1c) values (glycated
hemoglobin) when measured by HPLC. HPLC is the gold standard for
evaluation of glycated hemoglobin in diabetes mellitus.

.0112
HEMOGLOBIN OGI
HEMOGLOBIN QUEENS
HBA1, LEU34ARG

See Sugihara et al. (1982), Moo-Penn et al. (1982), and Yongsuwan et al.
(1987). This has been shown to be a mutation of the HBA1 gene (Cash et
al., 1989).

.0113
HEMOGLOBIN OLEANDER
HBA1, GLU116GLN

See Schneider et al. (1980).

.0114
HEMOGLOBIN OTTAWA
HEMOGLOBIN SIAM
HBA1, GLY15ARG

See Vella et al. (1974) and Pootrakul et al. (1974).

Yodsowan et al. (2000) studied this variant in a 21-year-old Thai female
and her mother. Turbpaiboon et al. (2002) reported a fourth case of Hb
Siam in a healthy Thai female and concluded that there is no
alpha-thalassemic effect of the variant.

.0115
HEMOGLOBIN OWARI
HBA1, VAL121MET

This is a neutral-to-neutral change; it was detected in the course of
mass screening by isoelectric focusing (Harano et al., 1986).

.0116
HEMOGLOBIN PERSPOLIS
HBA1, ASP64TYR

See Rahbar et al. (1976).

.0117
HEMOGLOBIN PETAH TIKVA
HBA1, ALA110ASP

See Honig et al. (1981).

.0118
HEMOGLOBIN PONTOISE
HEMOGLOBIN J (PONTOISE)
HBA1, ALA63ASP

See Thillet et al. (1977) and Gonzalez-Redondo et al. (1987).

.0119
HEMOGLOBIN PORT PHILLIP
HBA1, LEU91PRO

See Brennan et al. (1977).

.0120
MOVED TO 141850.0055
.0121
HEMOGLOBIN Q (INDIA)
HBA1, ASP64HIS

See Sukumaran et al. (1972) and Schmidt et al. (1976).

.0122
HEMOGLOBIN Q (IRAN)
HBA1, ASP75HIS

See Lorkin et al. (1970), Lie-Injo et al. (1979), and Higgs et al.
(1980).

.0123
MOVED TO 141850.0052
.0124
HEMOGLOBIN REIMS
HBA1, GLU23GLY

See Bardakdjian-Michau et al. (1989).

.0125
HEMOGLOBIN RUSS
HBA1, GLY51ARG

See Huisman and Sydenstricker (1962) and Reynolds and Huisman (1966).
This has been shown to be a mutation of the HBA1 gene (Cash et al.,
1989).

.0126
HEMOGLOBIN SASSARI
HBA1, ASP126HIS

Masala et al. (1987) first described this variant as an
electrophoretically slow-moving hemoglobin in 2 brothers affected by
erythrocytosis with slight microcytosis. In a large screening program
involving 20,000 people in the city of Sassari and its surrounding area
in Sardinia, Masala (1992) found the variant in 3 other apparently
unrelated subjects. A male of German origin was identified by
Bardakdjian-Michau et al. (1990) as a carrier of the same mutation.
Sanna et al. (1994) demonstrated that the adult variant has increased
oxygen affinity, a dramatic reduction of homotropic interactions, and a
significant decrease of the effect of 2,3-diphosphoglycerate (35% lower
than that observed for Hb A). The fetal variant also showed increased
oxygen affinity compared with normal Hb F and an almost abolished
heme-heme interaction.

Paglietti et al. (1998) demonstrated that Hb Sassari results from a GAC
(asp)-to-CAC (his) mutation in the HBA1 gene.

.0127
HEMOGLOBIN SAVARIA
HBA1, SER49ARG

See Szelenyi et al. (1980), Juricic et al. (1985), Ojwang et al. (1985),
and Suarez et al. (1985).

.0128
HEMOGLOBIN SAWARA
HBA1, ASP6ALA

No pathologic effects were observed (Sumida et al., 1973; Sumida, 1975).

.0130
HEMOGLOBIN SETIF
HBA1, ASP94TYR

See Wajcman et al. (1972), Nozari et al. (1977), Al-Awamy et al. (1985),
and Abdo (1989). Schiliro et al. (1991) found this hemoglobin variant in
Sicily.

Dincol et al. (2003) stated that Hb Setif was first described in an
Algerian family (Wajcman et al., 1972) and subsequently in Iranian,
African, Saudi Arabian, and Maltese populations. They identified the
variant in a Turkish family. Heterozygotes were asymptomatic.

.0131
HEMOGLOBIN SHAARE ZEDEK
HBA1, LYS56GLU

See Abramov et al. (1980).

.0132
HEMOGLOBIN SHENYANG
HBA1, ALA26GLU

See Zeng et al. (1982) and Yi et al. (1989).

.0133
HEMOGLOBIN SHIMONOSEKI
HEMOGLOBIN HIKOSHIMA
HBA1, GLN54ARG

See Yamaoka et al. (1960) and Hanada and Rucknagel (1964).

.0134
HEMOGLOBIN SHUANGFENG
HBA1, GLU27LYS

See Liang et al. (1981).

.0135
HEMOGLOBIN SINGAPORE
HBA1, ARG141PRO

See Clegg et al. (1969).

.0137
HEMOGLOBIN ST. CLAUDE
HBA1, LYS127THR

See Vella et al. (1974).

.0138
HEMOGLOBIN ST. LUKE'S
HBA1, PRO95ARG

See Bannister et al. (1972).

Felice (2003) cited evidence that Hb St. Luke's is a mutation of the
HBA1 gene.

.0139
HEMOGLOBIN STANLEYVILLE-II
HBA1, ASN78LYS

See Van Ros et al. (1968), North et al. (1980), and Rhoda et al. (1983).
Costa et al. (1991) described a family with 1 homozygote and 3
heterozygotes for Hb Stanleyville II. The pattern of restriction
fragments demonstrated an associated 3.7-kb alpha-globin gene deletion.

.0140
HEMOGLOBIN STRUMICA
HEMOGLOBIN SERBIA
HBA1, HIS112ARG

See Niazi et al. (1975) and Beksedic et al. (1975).

.0143
HEMOGLOBIN SUNSHINE SETH
HBA1, ASP94HIS

See Schroeder et al. (1979).

.0144
HEMOGLOBIN SURESNES
HBA1, ARG141HIS

See Poyart et al. (1976) and Saenz et al. (1978).

.0145
HEMOGLOBIN SWAN RIVER
HBA1, ASP6GLY

See Moo-Penn et al. (1987). Harano et al. (1996) observed this variant
in a Japanese man with mild polycythemia.

.0147
HEMOGLOBIN THAILAND
HBA1, LYS56THR

See Pootrakul et al. (1977).

.0148
HEMOGLOBIN TITUSVILLE
HBA1, ASP94ASN

See Schneider et al. (1975).

.0149
HEMOGLOBIN TOKONAME
HBA1, LYS139THR

See Harano et al. (1983).

.0150
HEMOGLOBIN TORINO
HBA1, PHE43VAL

See Beretta et al. (1968) and Prato et al. (1970).

.0151
HEMOGLOBIN TOTTORI
HBA1, GLY59VAL

See Nakatsuji et al. (1981).

.0152
HEMOGLOBIN TOYAMA
HEINZ BODY HEMOLYTIC ANEMIA
HBA1, LEU136ARG

This hemoglobin variant is associated with congenital Heinz body anemia
(Ohba et al., 1987).

.0153
HEMOGLOBIN TWIN PEAKS
HBA1, LEU113HIS

See Guis et al. (1985). This has been shown to be a mutation of the HBA1
gene (Cash et al., 1989).

.0154
HEMOGLOBIN UBE-2
HBA1, ASN68ASP

See Miyaji et al. (1967). In Turkey, Bilginer et al. (1984) found the
first instance of Hb Ube-2 outside Japan. It occurred in other members
of the family.

Cotton et al. (2000) found this rare variant during universal neonatal
screening. The patients had normal hematologic parameters. The variant
was found in twins and an older sister and in the father; both parents
were of Belgian ancestry.

Shin et al. (2002) described the disorder in a Taiwanese subject.

.0155
HEMOGLOBIN UBE-4
HBA1, GLU116ALA

See Ohba et al. (1978).

.0156
HEMOGLOBIN WESTMEAD
HBA1, HIS122GLN

This variant was found in a Chinese woman (Fleming et al., 1980). See
Liang et al. (1988).

.0157
HEMOGLOBIN WINNIPEG
HBA1, ASP75TYR

See Vella et al. (1973) and Nakatsuji et al. (1983). This has been shown
to be a mutation of the HBA1 gene (Cash et al., 1989).

.0158
HEMOGLOBIN WOODVILLE
HBA1, ASP6TYR

Since alpha-6 asp is involved in salt linkage with alpha-127 lys of the
same chain, the increased oxygen affinity of hemoglobin variants at this
position probably reflects loss of this salt bridge in the deoxy state.
Similar changes have been observed for Hb St. Claude which also cannot
form the salt bridge because of substitution of threonine for lysine at
alpha-127. See Como et al. (1986).

.0159
HEMOGLOBIN WUMING
HEMOGLOBIN J (WENCHANG-WUMING)
HBA1, LYS11GLN

See Zeng et al. (1981). Qualtieri et al. (1995) found this
fast-migrating hemoglobin variant in a pregnant woman living in Italy.

.0160
HEMOGLOBIN ZAMBIA
HBA1, LYS60ASN

See Barclay et al. (1969).

.0161
HEMOGLOBIN BELLIARD
HBA1, LYS56ASN

See Wajcman et al. (1990).

.0162
HEMOGLOBIN TONOSHO
HBA1, ALA110THR

In the course of measuring hemoglobin A1c by automated cation exchange
high performance liquid chromatography, Ohba et al. (1990) detected a
new alpha-chain variant: substitution of alanine by threonine at
position 110. The abnormal alpha chain comprised about 14% of the total
alpha chain.

.0163
HEMOGLOBIN FUKUTOMI
HBA1, ASP126VAL

This hemoglobin, which has a high affinity for oxygen, was detected in a
Japanese male during a screening survey. The proband was a 53-year-old
man with liver cirrhosis and hemorrhagic gastritis (Hidaka et al.,
1990).

.0164
HEMOGLOBIN PORT HURON
HBA1, LYS56ARG

Zwerdling et al. (1991) investigated the structural abnormality of a
putative Hb E detected in an African American family with no apparent
Asian ancestry. The tryptic peptide map formed by high performance
liquid chromatography showed that the electrophoretic variant was indeed
the beta glu26-to-lys mutation of Hb E. In addition, however, the
tryptic map showed an abnormal alpha peptide. The second mutation was a
substitution of arginine for lysine at residue 56 of the alpha chain.
The variant was clinically silent.

.0166
HEMOGLOBIN PAVIE
HBA1, VAL135GLU

See Wajcman et al. (1990).

.0167
HEMOGLOBIN QUESTEMBERT
HBA1, SER131PRO

See Wajcman et al. (1990, 1993).

.0168
HEMOGLOBIN THIONVILLE
HBA1, NH2 EXTENSION, VAL1GLU

See Vasseur et al. (1990). Substitution of glutamic acid for valine as
the first residue in the mature protein is accompanied by retention of
the initiator methionine residue. This may be the only known hemoglobin
variant with an NH2-extension in the alpha-globin chain. Hb Marseille
(141900.0171), Hb Doha (141900.0069), and Hb South Florida (141900.0266)
are examples of hemoglobin variants with an NH2-extension due to
retention of the initiator methionine in the beta-globin chain. Each is
due to mutation in the first or second residue of the mature protein.
Vasseur et al. (1992) found that elongation of the NH2-terminus of the
alpha-chain, due to inhibition of cleavage of the initiator methionine
which is then acetylated, modifies the 3-dimensional structure of
hemoglobin at a region that is known to have an important role in the
allosteric regulation of oxygen binding. Hb Thionville has a lowered
affinity for oxygen. In contrast, response to 2,3-diphosphoglycerate is
normal.

.0169
HEMOGLOBIN KANAGAWA
HBA1, LYS40MET

In the course of a high performance liquid chromatography survey of Hb
A1c, Miyashita et al. (1992) detected a new hemoglobin in a 70-year-old
Japanese male with cerebral infarction and erythremia. Further studies
revealed a lys40-to-met mutation. The variant showed increased oxygen
affinity, decreased heme-heme interaction, and a lowered
2,3-diphosphoglycerate effect.

(Erythemia, a now almost obsolete synonym for polycythemia and
erythrocytosis, means increased red blood cell mass.)

.0170
HEMOGLOBIN TURRIFF
HBA1, LYS99GLU

In a diabetic woman of Scottish ancestry, Langdown et al. (1992)
detected a new hemoglobin variant in the course of determining Hb A1c by
high performance liquid chromatography. The abnormal hemoglobin
chromatographed with the Hb A1c fraction. Family studies showed that a
lys99-to-glu mutation, which was not associated with any hematologic
disturbance, had occurred de novo. An AAG-to-GAG mutation was presumed
and was not assigned to either the alpha-2- or alpha-1-globin chain.

The Hb A(1c) level in the patient of Langdown et al. (1992) was found to
be very high. In a Japanese individual, Harano et al. (2003) likewise
found an unexpectedly high Hb A(1c) level as measured by an automatic Hb
A(1c) analyzer and found by DNA sequencing a change in the first
nucleotide of codon 99 (AAG-GAG) of the Hb A1 gene.

.0171
HEMOGLOBIN ZAIRE
HBA1, 15-BP TANDEM REPEAT

Hemoglobin Zaire was found in a 36-year-old patient from Zaire during a
systematic hemoglobin study. Wajcman et al. (1992) demonstrated that the
abnormality was the insertion of 5 amino acids--his, leu, pro, ala,
glu--between glu116 and phe117 of the alpha-globin chain. This sequence
represented a tandem repeat of the 5 amino acid residues from 112
through 116, located at the end of the GH corner of the molecule.
Hemoglobin Grady (141800.0045) involves the insertion of 3 amino acids
as repeats of residues 116, 117 and 118. Unequal crossing over between
alleles rather than between the separate alpha-1 and alpha-2 loci was
thought to be the mechanism in that case and possibly in the case of Hb
Zaire as well.

.0172
HEMOGLOBIN LUTON
HBA1, HIS89LEU

In a newborn infant and the father, a 35-year-old Pakistani man,
Williamson et al. (1992) described a new hemoglobin with high oxygen
affinity. The high affinity hemoglobin mutation was identified by HPLC
peptide mapping and amino acid sequencing; leucine was substituted for
histidine at amino acid position 89. The mutation occurred at the end of
the F helix (FG1), a part of the hemoglobin structure critical in
determining oxygen affinity since it is directly linked to the heme iron
through the proximal histidine residue F8. This was the first example of
a mutation at this position of the alpha chain of hemoglobin, although
there were 2 high affinity mutants that involved the structurally
equivalent amino acid (beta94 asp) of the beta chain: Hb Barcelona
(beta94 his; 141900.0016) and Hb Bunbury (beta94 asn; 141900.0035). The
new hemoglobin was called Hb Luton for the name of the hospital where
the proband was originally treated. The proband was a neonate in whom 2
abnormal hemoglobin bands were found, the 2 bands being the mutant forms
of fetal and adult hemoglobins containing the anomalous alpha globin.
The father had microcytosis as well as mild polycythemia and was shown
to have an accompanying alpha-thalassemia trait due to deletion of a
single alpha-globin gene.

.0173
HEMOGLOBIN OZIERI
HBA1, ALA71VAL

During a screening for hemoglobinopathies in Sardinia, Ferranti et al.
(1993) found a new 'silent' hemoglobin variant in 5 apparently unrelated
newborn babies. The variant was detected by means of isoelectric
focusing (IEF), and further study revealed a valine for alanine
substitution at position 71 of the alpha-globin chain. The substitution
indicated that a C-to-T transition had occurred in the GCG codon for
alanine which contains one of the 35 unmethylated CpG dinucleotides of
the HBA1 gene. This observation brought to 13 the number of variants due
to mutation in the CpGs of the HBA1 gene and raised the possibility that
unmethylated CpGs, like methylated ones, may be hotspots for mutations.

.0174
HEMOGLOBIN ADANA
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA1, GLY59ASP

In 3 Turkish children with severe thalassemia, Curuk et al. (1992) found
a GGC-to-GAC mutation in codon 59 of the HBA1 gene resulting in a
replacement of glycine by aspartic acid. The combination of an
alpha-thal-1 deletion with the unstable Hb Adana resulted in a severe
type of Hb H disease (613978).

.0175
HEMOGLOBIN AL-AIN ABU DHABI
HBA1, GLY18ASP

During a routine program of hemoglobin screening performed in the United
Arab Emirates, Abbes et al. (1992) found an electrophoretically
fast-moving variant in a 9-month-old girl and in several members of her
family. Amino acid sequencing demonstrated that the new variant had a
gly18-to-asp substitution. Its functional properties were normal.

.0176
HEMOGLOBIN POITIERS
HBA1, HIS45ASP

Hb Poitiers was discovered by Bardakdjian et al. (1994) in a 9-year-old
French Caucasian boy who suffered from chronic anemia. The molecular
defect consists of a missense mutation at codon 45 of the HBA1 gene,
changing histidine to aspartate. Hb Poitiers displays a 2-fold increased
oxygen affinity, a slightly decreased heme-heme interaction, and a
slightly faster autooxidation rate. In adult hemoglobin (Hb A), the
histidine residue at position 45 of the alpha-globin gene is the only
polar contact between the heme group and globin. This position, however,
seems to allow for moderate variation without dramatic consequences on
the function of hemoglobin. His45 is replaced by glutamine in Hb Bari
(141800.0009) and by arginine in Hb Fort de France (141800.0034).

.0177
MOVED TO 141850.0062
.0178
HEMOGLOBIN CAEN
HBA1, VAL132GLY

Wajcman et al. (1993) discovered the Hb Caen variant in a 25-year-old
French Caucasian woman suffering from a mild chronic hemolytic anemia.
Trypsin degradation of the isolated hemoglobin alpha chain followed by
high performance liquid chromatography indicated that the valine residue
at position 132 was replaced by glycine.

.0179
HEMOGLOBIN YUDA
HBA1, ALA130ASP

Hb Yuda was discovered in a 65-year-old Japanese female with
noninsulin-dependent diabetes mellitus (Fujisawa et al., 1992). Gas
phase Edman degradation indicated that the abnormal hemoglobin alpha
chain has a substitution of aspartic acid for alanine at residue 130. Hb
Yuda has a very low oxygen affinity and slightly decreased cooperative
subunit interaction.

.0180
HEMOGLOBIN CAPA
HBA1, ASP94GLY

Hb Capa was discovered in a 28-year-old female in Turkey who was being
treated for chronic iron deficiency anemia. The hemoglobin showed
abnormal electrophoretic mobility and was mildly unstable in a heat
denaturation test. The molecular change was a GAC-to-GGC transition in
codon 94, resulting in substitution of glycine for aspartic acid. Three
other substitutions of asp-94 are known: Hb Setif (141800.0130), Hb
Titusville (141800.0148), and Hb Sunshine Seth (141800.0143). All 4
variants exhibit mild instability.

.0181
HEMOGLOBIN MONTEFIORE
HBA1, ASP126TYR

Wajcman et al. (1992) demonstrated an asp126-to-tyr change in the HBA1
gene in an individual of Puerto Rican descent. At physiologic pH (7.4),
the oxygen binding of the patient's red blood cells revealed a 40%
reduction. Hb Montefiore appears to have lower cooperativity than other
characterized alpha-126 mutants: aspartic acid is replaced by asparagine
in Hb Tarrant (141800.0146), by histidine in Hb Sassari (141800.0126),
and by valine in Hb Fukutomi (141800.0163).

.0182
HEMOGLOBIN ROUEN
HEMOGLOBIN ETHIOPIA
HBA1, TYR140HIS

A tyr140-to-his mutation in the HBA1 gene was discovered and
characterized in a French patient with polycythemia vera by Wajcman et
al. (1992) and in a newborn baby of Ethiopian descent by Webber et al.
(1992). This mutation provides an example of an alteration of the
C-terminus of the alpha chain, a region involved in the mechanisms of
allosteric regulation. Hb Rouen has increased oxygen affinity and
decreased cooperativity. A complementary tyr145-to-his mutation (Hb
Bethesda; 141900.0022) in the hemoglobin beta chain has more dramatic
effects, suggesting that the alpha and beta chains play unequal roles in
the overall function of hemoglobin.

.0183
HEMOGLOBIN MELUSINE
HBA1, PRO114SER

Hb Melusine was found in an Algerian patient during a systematic
screening for hemoglobinopathies in Luxembourg. Using isoelectric
focusing and reverse phase high performance liquid chromatography
(RP-HPLC), Wajcman et al. (1993) determined that the molecular mutation
at amino acid position 114 of the HBA1 gene changed the residue from
proline to serine.

.0184
HEMOGLOBIN TAYBE
HBA1, THR38DEL OR THR39DEL

Girodon et al. (1992) reported the characterization of Hb Taybe, a
hemoglobin variant discovered in a young Arabic woman suffering since
birth from a severe and highly regenerative hemolytic anemia. DNA
amplification and sequencing of the HBA1 gene indicated a 3-bp deletion
(encoding threonine) at amino acid position 38 or 39. This variant
increases the hydrophobicity of the amino acid chain, and it is quite
unstable.

.0185
HEMOGLOBIN CEMENELUM
HBA1, ARG92TRP

Wajcman et al. (1994) described a missense mutation involving the same
codon as that involved in Hb Chesapeake (141800.0018), the first high
oxygen affinity hemoglobin variant to be described in association with
polycythemia (Charache et al., 1966). Hb Chesapeake has an arg92-to-leu
substitution; Hb Cemenelum has an arg92-to-trp substitution. Hb J (Cape
Town) (141800.0063) has a substitution (arg92-to-gln) in the same codon.
Hb Cemenelum was discovered in a French diabetic patient with no
hematologic abnormalities. The purified abnormal hemoglobin, like Hb J
(Cape Town), displayed only a 1.5- to 2-fold increased oxygen affinity.
The findings demonstrate that the degree to which the functional
properties are altered by changes in key residues at the alpha-beta
interface depends upon the specific residue occupying this position.

.0186
HEMOGLOBIN RAMONA
HBA1, TYR24CYS

Hb Ramona was accidentally detected by isoelectrofocusing in a pregnant
woman of part Spanish descent; its mobility was slightly faster than
that of Hb A. A TAT-to-TGT change was found at codon 24, corresponding
to a replacement of tyrosine by cysteine.

.0187
HEMOGLOBIN TATRAS
HBA1, LYS7ASN

In a 72-year-old woman born in Czechoslovakia, Wajcman et al. (1994)
found a lys7-to-asn mutation when investigating the basis for an
abnormal level of Hb A1c. No abnormal hematologic features were
observed.

.0188
HEMOGLOBIN LISBON
HBA1, GLU23ASP

In a 31-year-old man of Portuguese origin who had suffered from diabetes
mellitus since the age of 15 years, Wajcman et al. (1994) found an
abnormal hemoglobin during measurement of Hb A1c by an
isoelectrofocusing study. There were no abnormal hematologic features.

.0189
HEMOGLOBIN ROANNE
HBA1, ASP94GLU

Kister et al. (1995) described a new hemoglobin variant in a 73-year-old
woman from Roanne in central France. She suffered from mild chronic
hemolytic anemia. An asp94-to-glu substitution was found in the alpha-1
chain. Aspartate-94 is involved in several contacts, both in the deoxy-
and oxy-structures of the hemoglobin.

.0190
HEMOGLOBIN MALHACEN
HBA1, ALA123SER

Kazanetz et al. (1995) observed this variant hemoglobin in an adult male
in Granada, Spain, who was evaluated because of severe iron deficiency
anemia. Sequencing of the HBA1 gene showed 2 nucleotide changes. One was
a simple polymorphism, as both GCG and GCT code for alanine (at codon
120). The second mutation was a GCC-to-TCC change at codon 123 resulting
in replacement of alanine by serine. The replacement caused slight
differences in the IEF and reversed-phase HPLC experiments, but the
stability of the hemoglobin was normal. Family studies were not
performed; thus, whether the 2 mutations were in coupling or repulsion
was not known.

.0191
HEMOGLOBIN TUNIS-BIZERTE
HBA1, LEU129PRO

In 3 members of a Tunisian family, Darbellay et al. (1995) identified a
leu129-to-pro substitution in the HBA1 gene by sequencing the entirety
of the HBA2 and HBA1 genes. In the heterozygous state, the variant was
manifested by microcytosis, whereas the homozygous state showed moderate
anemia with marked microcytosis.

.0192
MOVED TO 141850.0068
.0193
HEMOGLOBIN BOIS GUILLAUME
HBA1, ALA65VAL

By tiny abnormalities observed during isoelectrofocusing, Wajcman et al.
(1995) identified this electrophoretically silent variant in 3 members
of a Caucasian-French family. This hemoglobin was the first alpha-chain
variant that involved position 64. In the beta chain, the corresponding
position, E14, is also occupied by an alanine residue; in Hb Seattle
(141900.0256), it is replaced by aspartic acid (ala70-to-asp).

.0194
HEMOGLOBIN MANTES-LA-JOLIE
HBA1, ALA79THR

Wajcman et al. (1995) found this variant hemoglobin during a systematic
study of the iron status in a 6-month-old baby and his mother who
originated from Chad in North Central Africa.

.0195
HEMOGLOBIN MOSELLA
HBA1, ALA111THR

Wajcman et al. (1995) found this variant in a 35-year-old pregnant woman
of Caucasian origin who lived in Luxembourg. The abnormal Hb was also
found in one of her daughters.

.0196
HEMOGLOBIN FUCHU-I
HBA1, HIS72TYR

At the Fuchu Municipal Medical Center in Tokyo, Harano et al. (1995)
identified 2 Hb variants in the course of assaying glycated hemoglobin,
Hb A(1c), of the peripheral blood by cation exchange HPLC. Structural
analyses demonstrated that 1 patient had a his72-to-tyr substitution and
the other an asn97-to-his substitution (141800.0197) of the alpha-globin
chain. These were named Hb Fuchu-I and Hb Fuchu-II, respectively. Both
were healthy adults.

.0197
HEMOGLOBIN FUCHU-II
HBA1, ASN97HIS

See 141800.0196.

.0198
HEMOGLOBIN GOUDA
HBA1, HIS72GLN

In a 54-year-old Dutch woman under treatment for diabetes mellitus,
Giordano et al. (1996) incidentally found a silent alpha-chain variant
on testing for glycated hemoglobin. A CAC-to-CAA transversion was
predicted to result in substitution of glutamine for histidine at
residue 72 in the HBA1 gene.

.0199
HEMOGLOBIN J (BISKRA)
HBA1, 24-BP DEL

Wajcman et al. (1998) described Hb J-Biskra, a variant hemoglobin
consisting of deletion of 24 nucleotides from the HBA1 gene and 8 amino
acid residues from the alpha-globin chain: residues 50-57, 51-58, or
52-59. This variant was mildly unstable in vitro only, and there was no
hematologic or biochemical evidence of hemolysis in affected family
members. Wajcman et al. (1998) stated that this was the largest deletion
reported to that time in a hemoglobin molecule that is expressed at an
almost normal level in the red blood cell.

.0200
HEMOGLOBIN GODAVARI
HBA1, PRO95THR

Hb Godavari is the fourth example of a substitution involving neutral
residues at position 95 of the alpha-1 chain. In all of these variants,
the electrophoretic pattern suggested that the structural modification
unmasks a charged residue in the alpha-1/beta-2 contact area. The other
examples are Hb Denmark Hill, pro95 to ala (141800.0027); Hb G
(Georgia), and pro95 to leu (141800.0038). Hb Godavari shared the same
electrophoretic properties as these variants, but displayed minimal
alterations of the oxygen-binding properties. Wajcman et al. (1998)
identified Hb Godavari in 2 families of different ethnic origin. The
first case, found in the Netherlands, involved an Indian patient. The
second case was identified a few months later in an African family from
Mali, living in France.

.0201
HEMOGLOBIN OITA
HBA1, HIS45PRO

Hamaguchi et al. (1998) reported a neutral (silent) hemoglobin variant,
designated Hb Oita, in which a change from CAC to CCC caused a
his45-to-pro substitution. In Hb Bari (141800.0009), his45 is replaced
by gln. In Hb Fort de France (141800.0034), his45 is replaced by arg. In
Hb Portiers (141800.0176), his45 is replaced by asp.

.0202
HEMOGLOBIN AGHIA SOPHIA
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA1, VAL62DEL

In a Greek child with Hb H disease (613978), Traeger-Synodinos et al.
(1999) found deletion of codon 62 of the alpha-1 gene, leading to
alpha-plus-thalassemia. Codon 62 encodes a valine residue at the E11
alpha helix, which is located in the interior of the heme pocket.
Substitutions of this valine with other amino acid residues in the alpha
as well as beta polypeptide chains lead, in the heterozygous carrier,
either to Hb M disease or to congenital nonspherocytic hemolytic anemia.
Traeger-Synodinos et al. (1999) assumed that deletion of val at position
62 disrupted the conformation of the alpha chain to such an extent that
the mutated subunit was rapidly removed by proteolysis. The final result
was an alpha-thalassemia phenotype rather than an unstable hemoglobin
syndrome. This conclusion was supported by the apparent absence of an
abnormal alpha chain in the peripheral blood of the patient. Hb Evans
(141850.0006) is a val62-to-met mutation of the HBA2 gene and was found
in a patient with mild hemolytic anemia. Four amino acid substitutions
at position 67(E11)val of the beta chain lead to instability of the Hb
tetramer and an anemia of variable degrees in the heterozygotes. One of
these substitutions, val67 to glu (141900.0163), results in the stable
Hb M-Milwaukee-I.

.0203
HEMOGLOBIN CHAROLLES
HBA1, HIS103TYR

Lacan et al. (1999) detected Hb Charolles in a 46-year-old patient who
presented with microcytosis and hypochromia. It was easily detected by
isoelectrofocusing and high performance liquid chromatography. It
accounted for 11% of the total hemoglobin. The amino acid change
resulted from a CAC-to-TAC change in codon 103.

.0204
HEMOGLOBIN ROUBAIX
HBA1, VAL55LEU

In a French family from the north of France, Prehu et al. (1999) found a
new HBA1 variant in 5 members. The variant was initially detected during
measurement of glycated hemoglobin in a woman originating from Roubaix.
Codon 55 in exon 2 was found to have a heterozygous change from GTT
(val) to CTT (leu). This was a neutral variant.

.0205
HEMOGLOBIN DOUALA
HBA1, SER3PHE

In a woman from Cameroon, Prehu et al. (2001) identified a new
hemoglobin variant, designated Hb Douala, with a C-to-T transition
(TCT-TTT) in the HBA1 gene, resulting in a ser3-to-phe (S3F) amino acid
substitution. The patient was also heterozygous for Hb S (141900.0243)
and for a 3.7-kb deletional alpha-thalassemia.

.0206
THALASSEMIA, ALPHA-PLUS
HBA1, 21-BP INS-DUP

In a patient of Iranian descent with the hematologic profile of
alpha-plus-thalassemia characterized by mild microcytosis, Waye et al.
(2001) found a 21-bp insertion/duplication that gave rise to a predicted
alpha-globin chain containing a duplication of amino acid residues
93-99.

.0207
THALASSEMIA, ALPHA-PLUS
HBA1, 33-BP DEL

In a patient of Greek descent with the hematologic profile of
alpha-plus-thalassemia characterized by mild microcytosis, Waye et al.
(2001) found a 33-bp deletion in the HBA1 gene resulting in a predicted
alpha-globin chain missing amino acid residues 64-74.

.0208
HEMOGLOBIN DELFZICHT
HBA1, ASN9LYS

Harteveld et al. (2002) reported a 69-year-old Dutch woman monitored for
diabetes mellitus in whom Hb A(L1c) analysis revealed a clinically
silent hemoglobin variant, asn9 to lys (N9K), due to an AAC-to-AAG
transversion in heterozygous state. The mutation was identical to that
found at the same position in the HBA2 gene that leads to a variant
named Hb Park Ridge (141850.0048).

.0209
HEMOGLOBIN SARATOGA SPRINGS
HBA1, LYS40ASN

In a 34-year-old Caucasian male of Swedish ancestry who lived in
Saratoga Springs, New York, Hoyer et al. (2003) identified a hemoglobin
variant with abnormal oxygen affinity, designated Hb Saratoga Springs.
There was no family history of erythrocytosis. The patient had no
smoking history. A change of codon 40 of the HBA1 gene from AAG to AAC
resulted in a lys40-to-asn (K40N) change. Lys40 is replaced by glu in Hb
Kariya (141800.0081), and by met in Hb Kanagawa (141800.0169). Both of
these hemoglobins had been shown to have increased oxygen affinity, but
neither was associated with erythrocytosis.

.0210
HEMOGLOBIN DIE
HBA1, VAL93ALA

In a 7-year-old girl living near the town of Die in southeast France,
Lacan et al. (2004) identified a val93-to-ala (V93A) mutation in the
HBA1 gene. The family was of French Caucasian origin.

.0211
HEMOGLOBIN BEZIERS
HBA1, LYS99ASN

In a 72-year-old woman of French Caucasian origin living in the city of
Beziers in the south of France, Lacan et al. (2004) identified a
lys99-to-asn (K99N) mutation in the HBA1 gene. The variant was found
during the determination of Hb A(1c) by high performance liquid
chromatography (HPLC) in this diabetic patient. Hematologic data were
normal, without hepatomegaly or splenomegaly.

.0212
HEMOGLOBIN BUFFALO
HBA1, HIS89GLN

In a 32-year-old Somali male living in the Netherlands who was being
monitored for diabetes mellitus, Harteveld et al. (2004) identified Hb S
(141900.0243) in heterozygous state and a heterozygous C-to-G
transversion in the HBA1 gene, resulting in a his89-to-gln (H89Q)
substitution. The H89Q mutation had previously been described in a
Yemenite woman and 2 apparently unrelated Somali males (Hoyer et al.,
2002), and had been designated Hb Buffalo. No hematologic abnormality
had been associated with the allelic variant in this or other cases. In
addition to Hb Buffalo, 4 amino acid substitutions had been reported at
codon 89: Hb Luton (his89 to leu; 141800.0172), Hb Villeurbanne (his89
to tyr; 141800.0213), Hb Tokyo (his89 to pro; 141800.0214), and Hb
Tamano (his89 to arg; 141800.0215).

.0213
HEMOGLOBIN VILLEURBANNE
HBA1, HIS89TYR

Deon et al. (1997) identified a his89-to-tyr (H89Y) mutation in the HBA1
gene as the defect in Hb Villeurbanne.

.0214
HEMOGLOBIN TOKYO
HBA1, HIS89PRO

Harteveld et al. (2004) stated that Hb Tokyo carries a his89-to-pro
(H89P) mutation in the HBA1 gene.

.0215
HEMOGLOBIN TAMANO
HBA1, HIS89ARG

Harteveld et al. (2004) stated that Hb Tamano carries a his89-to-arg
(H89R) mutation in the HBA1 gene.

.0216
HEMOGLOBIN RICCARTON
HBA1, GLY51SER

In a 4-year-old Caucasian boy investigated for fatigue and microcytosis,
Brennan et al. (2005) found a GGC-to-AGC transition at codon 51 in the
HBA1 gene, resulting in a gly51-to-ser substitution (G51S). The mutation
was thought not to be the cause of the microcytosis as it was detected
also in the boy's father who had normal red cell indices.

.0217
HEMOGLOBIN OEGSTGEEST
HBA1, CYS104SER

In an 8-year-old black female of Surinamese origin with a mild
alpha-thalassemia phenotype, Harteveld et al. (2005) identified
homozygosity for a TGC-to-AGC transversion in the HBA1 gene, resulting
in a cys104-to-ser substitution. Cysteine-104 is involved in alpha/beta
globin contact and had been described as a critical amino acid of the
HBA2 chain when substituted by a tyrosine (cys104 to tyr) in Hb
Sallanches (141850.0031).

.0218
HEMOGLOBIN LAMEN ISLAND
HBA1, 149709T-C

De Gobbi et al. (2006) studied 148 individuals from Melanesia with
alpha-thalassemia, including 5 with HbH disease, in whom none of the
theretofore described molecular defects could be found. The pattern of
inheritance suggested that individuals with HbH disease were homozygous
for a codominant defect, referred to as (alpha-alpha)T, causing
alpha-thalassemia with a predicted genotype of
(alpha-alpha)T/(alpha-alpha)T. In situ RNA hybridization in erythroid
cells from an affected individual from Lamen Island (Vanuatu) detected
substantially fewer nuclear transcripts from the alpha-globin genes than
from the beta-globin genes. DNA FISH in 2 affected individuals showed
that the alpha-globin cluster was present at its normal location of
chromosome 16, and no deletions or chromosomal rearrangements were
detected in any of these individuals. Linkage analysis showed that the
disease phenotype in individuals was derived from telomeric chromosome
16 T. Only the C allele of SNP195 (C or T, located at coordinate 149709)
segregated with thalassemia in the affected families and showed complete
association with the (alpha-alpha)T haplotype. This allele was not found
in a separate analysis of 131 nonthalassemic Melanesian individuals.
SNP195 changes the sequence 5-prime-TAATAA-3-prime (T allele) to
5-prime-TGATAA-3-prime (C allele), potentially creating a new binding
site for the key erythroid transcription factor GATA1. GATA1 binds at
the C allele of SNP195 in vivo. SNP195 creates a new promoter-like
element between the upstream regulatory elements and their cognate
promoters. This element, when activated, causes significant
downregulation of the alpha-D, alpha-2, and alpha-1 genes that lie
downstream, thereby causing alpha-thalassemia.

.0219
ALPHA-THALASSEMIA
HBA1, 1-BP DEL, 354C

In a newborn of mixed black and Chinese descent who carried the
Southeast Asian alpha-0-thal deletion, Eng et al. (2006) also found a
1-bp deletion of cysteine from codon 78 in exon 2 of the HBA1 gene,
resulting in a frameshift and premature termination at codon 83.

.0220
HEMOGLOBIN AUCKLAND
HBA1, HIS87ASN

In a 27-year-old woman with mild compensated hemolytic anemia, Brennan
and Matthews (1997) identified Hb Auckland, a his87-to-asn substitution
in the HBA1 gene.

.9999
HEMOGLOBIN ALPHA VARIANTS, MOLECULAR DEFECT UNKNOWN

HEMOGLOBIN J (INDIA). See Raper (1957).

HEMOGLOBIN J (MALAYA). See Lehmann (1962).

HEMOGLOBIN K (CALCUTTA). Fast hemoglobin. See Lehmann (1962).

HEMOGLOBIN K (MADRAS). See Ager and Lehmann (1957).

HEMOGLOBIN KARAMOJO. See Allbrook et al. (1965).

HEMOGLOBIN L (BOMBAY). See Sukumaran and Pik (1965).

HEMOGLOBIN M (RESERVE). Reduced oxygen affinity and decreased reversible
oxygen-binding capacity (Overly et al., 1967).

HEMOGLOBIN N, ALPHA TYPE. An alpha chain anomaly was deduced from
molecular hybridization experiments with canine hemoglobin (Silvestroni
et al., 1963). Other hemoglobin N variants have a beta change.

HEMOGLOBIN NICOSIA. See Fessas et al. (1965).

*FIELD* SA
Al-Awamy et al. (1985); Baklouti et al. (1988); Barg et al. (1982);
Barton et al. (1982); Brittenham et al. (1980); Davis et al. (1979);
Dincol et al. (1994); Dozy et al. (1979); Embury et al. (1979); Harano
et al. (1983); Harano et al. (1983); Harano et al. (1983); Harano
et al. (1984); Harano et al. (1982); Hess et al. (1983); Higgs et
al. (1981); Hill et al. (1985); Huisman and Miller (1976); Kan et
al. (1979); Kielman et al. (1993); Li et al. (1990); Liang et al.
(1981); Liebhaber et al. (1980); Marinucci et al. (1979); Meloni et
al. (1980); Ohba et al. (1978); Phillips et al. (1979); Phillips et
al. (1980); Pobedimskaya et al. (1994); Priest et al. (1989); Proudfoot
and Maniatis (1980); Romao et al. (1992); Schroeder and Jones (1965);
Shimizu et al. (1965); Southern (1975); Vella et al. (1974); Wainscoat
et al. (1983); Wajcman et al. (1989); Wajcman et al. (1990); Wajcman
et al. (1992); Wajcman et al. (1992); Wajcman et al. (1993); Wajcman
et al. (1990); Weatherall and Clegg (1979); Zimmer et al. (1980)
*FIELD* RF
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Y.; Kister, J.; Galacteros, F.; Wajcman, H.: Hb Al-Ain Abu Dhabi
[alpha-18 (A16) gly-to-asp]: a new hemoglobin variant discovered in
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2. Abdo, M. Z.: Hb Setif (alpha94(G1)asp-to-tyr) in a Saudi Arabian
family. Hemoglobin 13: 737-742, 1989.

3. Abramov, A.; Lehmann, H.; Robb, L.: Hb Shaare Zedek (alpha56 E5
lys-to-glu). FEBS Lett. 113: 235-237, 1980.

4. Abramson, R. K.; Rucknagel, D. L.; Shreffler, D. C.; Saave, J.
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5. Adams, J. G., III: Hemoglobin Ann Arbor: disturbance in the coordinated
biosynthesis of globin chains? Ann. N.Y. Acad. Sci. 241: 232-241,
1974.

6. Adams, J. G., III; Winter, W. P.; Rucknagel, D. L.; Spencer, H.
H.: Biosynthesis of hemoglobin Ann Arbor: evidence for catabolic
and feedback regulation. Science 176: 1427-1429, 1972.

7. Ager, J. A. M.; Lehmann, H.: Haemoglobin K in an East Indian and
his family. Brit. Med. J. 1: 1449-1450, 1957.

8. Ager, J. A. M.; Lehmann, H.; Vella, F.: Haemoglobin 'Norfolk':
a new haemoglobin found in an English family. Brit. Med. J. 2: 539-541,
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9. Ahmad, A.; Naqvi, S.; Ehsanullah, S.; Zaidi, Z. H.: Abnormal hemoglobins-11
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10. Al-Awamy, B.; Niazi, G. A.; Wilson, J. B.; Huisman, T. H. J.:
Hb Setif or alpha94(G1)asp-to-tyr observed in a Saudi Arabian family. Hemoglobin 9:
87-90, 1985.

11. Al-Awamy, B. H.; Niazi, G. A.; Naeem, M. A.; Wilson, J. B.; Huisman,
T. H. J.: Hemoglobin Handsworth or alpha18(A16)gly-to-arg in a Saudi
newborn. Hemoglobin 9: 183-186, 1985.

12. Alberti, R.; Mariuzzi, G. M.; Artibani, L.; Bruni, E.; Tentori,
L.: A new haemoglobin variant: J-Rovigo alpha 53 (E-2) alanine to
aspartic acid. Biochim. Biophys. Acta 342: 1-4, 1974.

13. Allbrook, D.; Barnicot, N. A.; Dance, N.; Lawler, S. D.; Marshall,
R.; Mungai, J.: Blood groups, haemoglobin and serum factors of the
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14. Allen, S. J.; O'Donnell, A.; Alexander, N. D. E.; Alpers, M. P.;
Peto, T. E. A.; Clegg, J. B.; Weatherall, D. J.: Alpha(+)-thalassemia
protects children against disease caused by other infections as well
as malaria. Proc. Nat. Acad. Sci. 94: 14736-14741, 1997.

15. Ameri, A.; Fairbanks, V. F.; Yanik, G. A.; Mahdi, F.; Thibodeau,
S. N.; McCormick, D. J.; Boxer, L. A.; McDonagh, K. T.: Identification
of the molecular genetic defect of patients with methemoglobin M Kankakee
(M-Iwate), alpha-87 (F8) his-to-tyr: evidence for an electrostatic
model of alpha-M hemoglobin assembly. Blood 94: 1825-1826, 1999.

16. Andersen, C. B. F.; Torvund-Jensen, M.; Nielsen, M. J.; de Oliveira,
C. L. P.; Hersleth, H.-P.; Andersen, N. H.; Pedersen, J. S.; Andersen,
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17. Assum, G.; Griese, E.-U.; Horst, J.: Detection of a restriction
site polymorphism within the human alpha-globin gene complex. Hum.
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19. Baglioni, C.; Lehmann, H.: Chemical heterogeneity of haemoglobin
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20. Baklouti, F.; Baudin-Chich, V.; Kister, J.; Marden, M.; Teyssier,
G.; Poyart, C.; Delaunay, J.; Wajcman, H.: Increased oxygen affinity
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21. Baklouti, F.; Francina, A.; Dorleac, E.; Baudin-Chich, V.; Gombaud-Saintonge,
G.; Plauchu, H.; Wajcman, H.; Delaunay, J.; Godet, J.: Asymptomatic
association of hemoglobin Dunn (alpha-6(A4)asp-to-asn) and hemoglobin
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22. Bannister, W. H.; Grech, J. L.; Plese, C. F.; Smith, L. L.; Barton,
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132. Harano, T.; Harano, K.; Imai, K.; Terunuma, S.: Hb Swan River
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133. Harano, T.; Harano, K.; Imai, N.; Ueda, S.; Seki, M.: An electrophoretically
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134. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Imai, K.; Seki,
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135. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Imai, K.; Seki,
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136. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Imai, K.; Tsuneshige,
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137. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Imai, K.; Tsuneshige,
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lys-to-glu) a new hemoglobin variant with an increased oxygen affinity. FEBS
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138. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Mori, H.; Imai,
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(FG4) arg-to-gln) first discovered in Japanese. Hemoglobin 7: 461-465,
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139. Harano, T.; Harano, K.; Shibata, S.; Ueda, S.; Mori, H.; Seki,
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140. Harano, T.; Harano, K.; Ueda, S.: Hb Owari (alpha121 (H4) val-to-met):
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141. Harano, T.; Harano, K.; Ueda, S.; Shibata, S.; Imai, K.; Ohba,
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oxygen affinity with amino acid substitution at alpha(1)-beta(2) contact. Hemoglobin 6:
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142. Harano, T.; Harano, K.; Uehara, S.; Matsushita, K.: Two new
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143. Hardison, R. C.; Sawada, I.; Cheng, J.-F.; Shen, C.-K. J.; Schmid,
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144. Harteveld, C. L.; Rozendaal, L.; Blom, N. A.; Lo-A-Njoe, S.;
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145. Harteveld, C. L.; Van Delft, P.; Akkermans, N.; Arkesteijn, S.;
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146. Harteveld, C. L.; Van Delft, P.; Plug, R. J.; Erjavec, Z.; Wajcman,
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147. Harteveld, C. L.; Wijermans, P. W.; de Ree, J. E. L. M.; Ter
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148. Hatton, C. S. R.; Wilkie, A. O. M.; Drysdale, H. C.; Wood, W.
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149. Hattori, Y.; Ohba, Y.; Suda, T.; Miura, Y.; Yoshinaka, H.; Miyaji,
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150. Hayashi, A.; Yamamura, Y.; Ogita, S.; Kikkawa, H.: Hemoglobin
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151. Headlee, M. G.; Nakatsuji, T.; Lam, H.; Wrightstone, R. N.; Huisman,
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152. Heller, P.: Hemoglobin M (Chicago) and M (Kankakee).In: Lehmann,
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153. Heller, P.; Weinstein, H. G.; Yakulis, V. J.; Rosenthal, I. M.
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154. Hess, J. F.; Fox, M.; Schmid, C.; Shen, C.-K. J.: Molecular
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155. Hidaka, K.; Iuchi, I.; Kobayashi, T.; Katoh, K.; Yaguchi, K.
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156. Higgs, D. R.; Goodbourn, S. E. Y.; Wainscoat, J. S.; Clegg, J.
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157. Higgs, D. R.; Hunt, D. M.; Drysdale, H. C.; Clegg, J. B.; Pressley,
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158. Higgs, D. R.; Vickers, M. A.; Wilkie, A. O. M.; Pretorius, I.-M.;
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159. Higgs, D. R.; Wainscoat, J. S.; Flint, J.; Hill, A. V. S.; Thein,
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160. Hill, A. V. S.; Bowden, D. K.; Trent, R. J.; Higgs, D. R.; Oppenheimer,
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162. Hollan, S. R.; Szelenyi, J. G.; Brimhall, B.; Duerst, M.; Jones,
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163. Hollan, S. R.; Szelenyi, J. G.; Lehmann, H.; Beale, D.: A Boston-type
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164. Honig, G. R.; Shamsuddin, M.; Tremaine, L. M.; Mason, R. G.;
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166. Honig, G. R.; Shamsuddin, M.; Zaizov, R.; Steinherz, M.; Solar,
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167. Honig, G. R.; Vida, L. N.; Shamsuddin, M.; Mason, R. G.; Schlumpf,
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168. Horst, J.; Assum, G.; Griese, E. U.; Eigel, A.; Hampl, W.; Kohne,
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169. Houjun, L.; Dexiang, L.; Zhiguo, L.; Ping, L.; Ly, L.; Ji, C.;
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170. Hoyer, J. D.; McCormick, D. J.; Snow, K.; Lawler, J.; Jadick,
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176. Huisman, T. H. J.; Wilson, J. B.; Gravely, M.; Hubbard, M.:
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177. Huntsman, R. G.; Hall, M.; Lehmann, H.; Sukumaran, P. K.: A
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223. Liang, C.-C.; Chen, S.-S.; Jia, P.-C.; Wang, L.-F.; Luo, H.-Y.;
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409. Waye, J. S.; Eng, B.; Patterson, M.; Carcao, M. D.; Chang, L.;
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414. Wilkie, A. O. M.; Higgs, D. R.; Rack, K. A.; Buckle, V. J.; Spurr,
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418. Winter, W. P.; Rucknagel, D. L.; Fielding, J.: Identification
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419. Wong, S. C.; Ali, M. A. M.; Pond, J. R.; Rubin, S. M.; Johnson,
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422. Yi, C. H.; Li, H. J.; Li, H. W.; Zhang, X. S.; Zhao, X. N.; Zhang,
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427. Zeng, Y.; Huang, S.; Liang, X.; Long, G.; Lam, H.; Wilson, J.
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428. Zeng, Y.; Huang, S.; Qiu, X.; Cheng, G.; Ren, Z.; Jin, Q.; Chen,
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429. Zeng, Y.; Huang, S.; Zhou, X.; Qiu, X.; Dong, Q.; Li, M.; Bai,
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430. Zhao, W.; Wilson, J. B.; Webber, B. B.; Kutlar, A.; Tamagnini,
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Chinese from Macau: identification of the GAG-to-GAT mutation in the
alpha-1-globin gene. Hemoglobin 14: 627-635, 1990.

431. Zhou, Z.; Chen, L.; Chen, P.; Zhang, K.; Wang, Y.: Hemoglobin
Hangzhou alpha64 (E13) asp-to-gly: a new variant found in China. Hemoglobin 11:
31-33, 1987.

432. Zimmer, E. A.; Martin, S. L.; Beverley, S. M.; Kan, Y. W.; Wilson,
A. C.: Rapid duplication and loss of genes coding for the alpha chains
of hemoglobin. Proc. Nat. Acad. Sci. 77: 2158-2162, 1980.

433. Zwerdling, T.; Williams, S.; Nasr, S. A.; Rucknagel, D. L.:
Hb Port Huron (alpha56(E5)lys-to-arg): a new alpha chain variant. Hemoglobin 15:
381-391, 1991.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Jaundice;
Cyanosis

HEMATOLOGY:
Alpha polypeptide hemoglobin chain;
Alpha-thalassemia silent carrier (3 normal genes);
Alpha-thalassemia with microcytosis (2 normal genes);
Alpha-thalassemia with microcytosis and hemolysis, Hb H disease (1
normal gene);
Alpha-thalassemia with fatal Hb Bart's hydrops fetalis (No normal
gene);
Polycythemia (e.g. Hb Chesapeake 141800.0018);
Unstable hemoglobin (e.g. Hb Contaldo 141800.0022);
Hemolysis (e.g. Hb Koelliker 141800.0083);
Methemoglobinemia (e.g. Hb M Boston 141800.0092);
Amelioration of SS disease (e.g. Hb Memphis 141800.0096);
Congenital Heinz body anemia (e.g. Hb Toyama 141800.0152)

LABORATORY ABNORMALITIES:
Decreased heme-heme interaction (e.g. Hb Kanagawa 141800.0169);
Increased oxygen affinity (e.g. Hb Nunobiki 141800.0109);
Reduced oxygen affinity (e.g. Hb Thionville 141800.0168);
Decreased reversible oxygen-binding capacity (e.g. Hb L (Bombay) 141800.9999)

MISCELLANEOUS:
Two alpha-globin genes - 5-prime or alpha-2 and 3-prime or alpha-1

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/18/2011

*FIELD* CN
Ada Hamosh - updated: 12/14/2012
Ada Hamosh - updated: 11/1/2012
Patricia A. Hartz - updated: 1/28/2010
Carol A. Bocchini - updated: 5/22/2009
Victor A. McKusick - updated: 9/19/2006
Ada Hamosh - updated: 7/21/2006
Victor A. McKusick - updated: 3/29/2006
Victor A. McKusick - updated: 10/11/2005
Victor A. McKusick - updated: 8/11/2005
Victor A. McKusick - updated: 5/11/2005
Victor A. McKusick - updated: 12/6/2004
Victor A. McKusick - updated: 8/6/2004
Victor A. McKusick - updated: 6/2/2004
Victor A. McKusick - updated: 1/20/2004
Victor A. McKusick - updated: 1/15/2004
Victor A. McKusick - updated: 9/2/2003
Victor A. McKusick - updated: 3/5/2003
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 6/3/2002
Victor A. McKusick - updated: 5/23/2002
Victor A. McKusick - updated: 2/27/2002
Victor A. McKusick - updated: 11/1/2001
Victor A. McKusick - updated: 10/11/2001
Victor A. McKusick - updated: 5/1/2000
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 7/14/1999
Ada Hamosh - updated: 4/21/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 2/9/1999
Ada Hamosh - updated: 6/12/1998
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 2/6/1998
Victor A. McKusick - updated: 8/27/1997

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
tpirozzi: 09/30/2013
alopez: 12/19/2012
terry: 12/14/2012
alopez: 11/2/2012
terry: 11/1/2012
alopez: 8/6/2012
alopez: 7/25/2011
carol: 6/9/2011
alopez: 5/13/2011
alopez: 1/28/2010
terry: 6/3/2009
carol: 5/22/2009
terry: 1/15/2009
terry: 1/14/2009
wwang: 10/4/2007
wwang: 10/3/2006
terry: 9/19/2006
alopez: 7/25/2006
terry: 7/21/2006
terry: 6/23/2006
terry: 3/29/2006
carol: 10/21/2005
wwang: 10/21/2005
terry: 10/11/2005
carol: 10/3/2005
terry: 8/11/2005
wwang: 6/7/2005
terry: 5/17/2005
wwang: 5/13/2005
terry: 5/11/2005
terry: 2/7/2005
tkritzer: 1/25/2005
terry: 12/6/2004
tkritzer: 8/10/2004
terry: 8/6/2004
tkritzer: 6/8/2004
terry: 6/2/2004
carol: 3/17/2004
tkritzer: 1/21/2004
terry: 1/20/2004
terry: 1/15/2004
cwells: 9/3/2003
terry: 9/2/2003
carol: 8/29/2003
carol: 8/25/2003
carol: 5/13/2003
terry: 4/17/2003
terry: 3/5/2003
terry: 3/3/2003
tkritzer: 12/10/2002
tkritzer: 10/7/2002
tkritzer: 10/3/2002
tkritzer: 10/2/2002
carol: 6/3/2002
terry: 6/3/2002
terry: 5/23/2002
cwells: 3/22/2002
cwells: 3/20/2002
terry: 2/27/2002
mcapotos: 11/1/2001
mcapotos: 10/26/2001
mcapotos: 10/11/2001
cwells: 5/31/2001
mcapotos: 2/19/2001
mcapotos: 2/15/2001
terry: 2/14/2001
mcapotos: 5/26/2000
mcapotos: 5/24/2000
terry: 5/1/2000
mcapotos: 2/7/2000
mcapotos: 2/4/2000
carol: 1/28/2000
mcapotos: 1/28/2000
mcapotos: 1/24/2000
terry: 1/19/2000
carol: 12/8/1999
mgross: 7/16/1999
terry: 7/14/1999
carol: 6/27/1999
terry: 4/30/1999
alopez: 4/21/1999
terry: 3/24/1999
carol: 3/9/1999
terry: 2/24/1999
mgross: 2/16/1999
mgross: 2/11/1999
terry: 2/9/1999
dkim: 7/21/1998
carol: 7/2/1998
alopez: 6/12/1998
terry: 6/5/1998
alopez: 5/14/1998
carol: 5/4/1998
terry: 4/30/1998
mark: 2/16/1998
terry: 2/6/1998
mark: 10/19/1997
jenny: 9/5/1997
terry: 8/27/1997
alopez: 7/31/1997
alopez: 7/29/1997
terry: 7/10/1997
mark: 7/10/1997
alopez: 7/10/1997
terry: 7/9/1997
terry: 7/7/1997
mark: 6/14/1997
terry: 11/15/1996
terry: 11/13/1996
mark: 4/12/1996
terry: 4/9/1996
mark: 2/13/1996
terry: 2/5/1996
mark: 11/17/1995
terry: 11/18/1994
jason: 7/29/1994
pfoster: 4/25/1994
mimadm: 4/17/1994
warfield: 4/8/1994

MIM 141850
*RECORD*
*FIELD* NO
141850
*FIELD* TI
*141850 HEMOGLOBIN--ALPHA LOCUS 2; HBA2
;;5-PRIME @ALPHA-GLOBIN GENE;;
ALPHA-GLOBIN LOCUS, SECOND;;
read moreMAJOR ALPHA-GLOBIN LOCUS
*FIELD* TX
Since at least as early as 1970, 2 alpha loci have been known to exist
in some humans (Brimhall et al., 1970): hemoglobins G (Pest) and J
(Buda) showed the existence of at least 2 alpha chains in the Hungarians
studied (141800.0041, 141850.0008), whereas hemoglobin J (Tongariki)
indicated that in Melanesians only 1 alpha locus exists (141800.0077).
The alpha locus is apparently double in Chinese (Kan, 1974), whereas in
American blacks, chromosomes with single or double alpha loci are about
equally frequent (Huisman, 1974). Rucknagel and Dublin (1974) estimated
that a chromosome with a single alpha locus has a frequency of about
0.27 in American blacks and about 0.36 in African blacks. Rucknagel and
Rising (1975) studied an American black family in which of 5 persons
heterozygous for hemoglobin G (Philadelphia), an alpha-chain mutant, 3
had about 30% Hb G and 2 had 40%. They suggested that the former persons
have 2 alpha hemoglobin loci and the latter persons 1 such locus. Three
members of a Hungarian family had 2 alpha-chain variants (Hb J Buda and
Hb G Pest), each variant accounting for 25% of hemoglobin, the rest
being Hb A (Brimhall et al., 1974). From studies of hemoglobin G
(Philadelphia), Baine et al. (1976) also concluded that there is
variability in the number of alpha-chain genes in the American black
population. In heterozygotes the proportion of Hb G (Philadelphia) was
trimodally distributed with modes at about 20%, 30%, and 40%. The
workers concluded that gene dosage accounts for this: 1 G gene out of 4
alpha genes leads to 20% Hb G; 1 G gene out of 3 alpha genes leads to
30% Hb G; 1 G gene out of 2 alpha genes or 2 G genes out of 4 alpha
genes leads to 40% Hb G. In Melanesians, Eng et al. (1974) observed
homozygous Hb Constant Spring and Hb A. The products of the 2
alpha-chain genes appear to have the same primary structure. Although
there is no direct proof, they are probably closely linked
(Politis-Tsegos et al., 1976). Unequal crossingover may be responsible
for the type of alpha-thalassemia with deleted alpha loci. From study of
Hb J(Mexico) in an Algerian family, Trabuchet et al. (1977) also
concluded that the alpha gene was duplicate in some chromosomes and
single in others. Two types of deletional alpha-plus-thalassemia are
identified by molecular genetic studies. One, termed leftward, shows a
deletion of 4.2 kb and removes the entire alpha-2 gene; the other,
termed rightward, has a deletion of 3.7 kb and gives rise to a hybrid
alpha-2/alpha-1 gene. The 3.7-kb rightward deletion can also remove the
entire alpha-1 gene and is 'possibly the most common mutation known to
produce a genetic disorder' (Bowden et al., 1987). It is prevalent in
most tropical and subtropical populations that have been studied,
including African and American blacks, Mediterraneans, Southeast Asians,
and some Pacific Island populations. In contrast, the 4.2-kb deletion of
the alpha-2 gene is very rare in African blacks and Mediterraneans. The
leftward one was found only in Asian cases until the report of a case in
East Sicily (Troungos et al., 1984).

El-Hazmi (1986) found several persons with the leftward deletion
alpha-thalassemia in Saudi Arabia, including homozygotes and
heterozygotes. Remarkably, in north coastal Papua New Guinea, the 4.2-kb
deletion is found in more than 80% of the population and appears to be
going to fixation (Oppenheimer et al., 1984). From comparison of the
level of hemoglobin Bart's at birth in homozygotes for each of the 2
deletions, Bowden et al. (1987) demonstrated that the alpha-2 gene, when
alone on the chromosome, reduces more alpha-globin than does the alpha-1
gene. (Since hemoglobin Bart's (142309) is a tetramer of gamma chains,
the level of this hemoglobin reflects in an inverse manner the amount of
alpha chains produced.) In a case of alpha-thalassemia, Whitelaw and
Proudfoot (1986) showed that the mutation in the 3-prime poly(A) site
leads to transcription of the mutant alpha-2 globin gene through into
the intergenic sequence past the normal termination site. They
interpreted these results as demonstrating that transcriptional
termination and 3-prime end processing of mRNA are coupled events for
the alpha-2 globin gene. Liebhaber et al. (1986) studied 8 separate
alpha-globin mutants mapped to the alpha-1 or the alpha-2 locus and
demonstrated that the alpha-2 gene encodes 2- to 3-fold more protein
than the alpha-1 gene. These results suggested that the human
alpha-globin cluster contains a major and a minor locus and that
deletions in the alpha-2 gene are more significant in the generation of
the alpha-thalassemia phenotype than are deletions in the alpha-1 gene.

N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2
is involved have been arbitrarily listed under HBA1 (141800).

Straub et al. (2012) reported a model for the regulation of nitric oxide
(NO) signaling by demonstrating that hemoglobin alpha, encoded by the
HBA1 (141800) and HBA2 genes, is expressed in human and mouse arterial
endothelial cells and enriched at the myoendothelial junction, where it
regulates the effects of NO on vascular reactivity. Notably, this
function is unique to hemoglobin alpha and is abrogated by its genetic
depletion. Mechanistically, endothelial hemoglobin alpha heme iron in
the Fe(3+) state permits NO signaling, and this signaling is shut off
when hemoglobin alpha is reduced to the Fe(2+) state by endothelial
cytochrome b5 reductase 3 (CYB5R3; 613213). Genetic and pharmacologic
inhibition of CYB5R3 increased NO bioactivity in small arteries. Straub
et al. (2012) concluded that their data revealed a mechanism by which
the regulation of the intracellular hemoglobin alpha oxidation state
controls nitric oxide synthase (NOS; see 163729) signaling in
nonerythroid cells. The authors suggested that this model may be
relevant to heme-containing globins in a broad range of NOS-containing
somatic cells.

*FIELD* AV
.0001
HEMOGLOBIN CONSTANT SPRING
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, TER142GLN

In this variant hemoglobin, named for the community in Jamaica where it
was first discovered (Clegg et al., 1971), alpha chains have 172 amino
acids rather than the normal 141. Clegg et al. (1971) suggested that
this may reflect a chain termination mutation. Hb Constant Spring
represents 1 to 2% of the hemoglobin of heterozygotes. When combined
with an alpha-thalassemia mutation, Hb H disease (613978) results. It is
the alpha-2 or 5-prime alpha-globin gene that is mutant in hemoglobin
Constant Spring. Hemoglobin Tak (141900.0279) is a termination defect of
the beta chain.

Hunt and Dayhoff (1972) searched 518 known protein sequences for a
31-amino acid sequence with the largest number of identities to that of
the extra piece on hemoglobin Constant Spring. The sequence that had the
greatest identity (9 amino acids) was the region 68-98 of the normal
alpha chain. See hemoglobin Wayne (141850.0004) for further discussion.

By use of allele-specific oligonucleotide probes, Kosasih et al. (1988)
demonstrated that Hb Constant Spring in a Batak Indonesian family was
due to replacement of T by C in the TAA terminal codon of the
alpha-2-globin gene, changing it to CAA, the codon for glutamine. This
resulted in read-through of the untranslated sequence of the mRNA.

Hsia et al. (1989) described a sensitive and specific DNA-based
screening test for improved detection of the Constant Spring variant
using polymerase chain reaction (PCR) and allele-specific
oligonucleotide slot-blot hybridization. Since the Constant Spring
protein is difficult to detect by electrophoresis, Hsia et al. (1989)
suspected that the true incidence of the Constant Spring variant may be
greater than previously suspected on the basis of protein
electrophoresis.

Laig et al. (1990) found Hb CS gene frequencies between 0.05 and 0.06 in
northeastern Thailand. The Lao-speaking populations of the Mekong River
basin were found to have the highest frequencies of the gene in
Southeast Asia.

To identify nondeletion types of Hb H disease in Guangxi, China, Wen et
al. (1992) designed 3 primers: one specific for HBA1 DNA, another
specific for HBA2 DNA, and a third that was common to the 2. In 27 of 59
Hb H cases (45.8%), it was possible to confirm the disorder as
nondeletional in type. Of these, 22 (81.5%) had the Hb Constant Spring
mutation and one had the Hb Quong Sze mutation (141850.0005). The
nondeletion Hb H disease in Guangxi seemed to be more severe than the
deletion types.

.0002
HEMOGLOBIN ICARIA
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, TER142LYS

Abnormally long alpha chain. Lysine is the 142nd amino acid. Glutamine
is the corresponding amino acid in the abnormally long alpha chain of Hb
Constant Spring (141850.0001), which like Hb Icaria is the result of a
terminator mutation (Clegg et al., 1974). The mutation is a TAA-to-AAA
change in codon 142 of the alpha-2 chain, converting it from 'stop' to
lysine. In a Yugoslavian teenager with moderate anemia with severe
microcytosis and hypochromia and 16% Hb H, Efremov et al. (1990)
identified the TAA-to-AAA mutation at codon 142 of the alpha-2 globin
gene. The patient also had an alpha-thalassemia-1 deletion of about 20.5
kb, common in Mediterranean populations. The one remaining alpha-1
globin gene was apparently able to compensate sufficiently for the loss
of the 3 alpha-globin genes to maintain a hemoglobin level of 8-9 g/dl.

The interaction of Hb Icaria with the Mediterranean type of alpha
thalassemia resulted in severe Hb H disease (613978); splenectomy
resulted in marked amelioration of clinical features (Kanavakis et al.,
1996).

.0003
HEMOGLOBIN KOYA DORA
HBA2, TER142SER

Excessive length of alpha-like chain (with at least 156 amino acids
rather than 141). De Jong et al. (1975) found that about 10% of members
of the Koya Dora tribe in Andhra Pradesh, India, carry this variant
hemoglobin. They found 2 persons with 2 alpha chain variants, Hb Rampa
and Hb Koya Dora, plus normal Hb A. This indicates that this population
carries 2 alpha chain loci. Hb Koya Dora resembles Hb Constant Spring
(141850.0001) in many respects including its alpha-thalassemia-like
expression. Serine is substituted at position 142 of the alpha-2 chain
(glutamine in Hb Constant Spring and lysine in Hb Icaria).

.0004
HEMOGLOBIN WAYNE
HBA2, LYS139ASN

Two hemoglobins, Hb W1 and Hb W2, with anomalous alpha chains were
observed in several members of a family. The alpha T-14 peptide was
replaced by a new peptide which was different in the 2. The sequence in
Hb A which was missing was thr-ser-lys-tyr-arg-COOH. In W1 it was
replaced by thr-ser-asn-thr-val-lys-leu-glu-pro-arg-COOH. Hb W2 had the
same peptide except that aspartic acid had been substituted for
asparagine in the third position. This was believed to represent the
result of enzymatic deamidation of Hb W1. This was the first reported
frameshift mutation in man. Deletion of a single nucleotide yields the
sequence observed in Hb W1. If the usual nucleotide sequence in the
alpha chain gene is ACX.UCX.AAA(G).UAC.CGU.UAA signifying
thr-ser-lys-tyr-arg-terminator, then hemoglobin Wayne has had a deletion
of the third nucleotide of codon 139 resulting in frameshift to
ACX.UCX.AAU.ACC.GUU.AAG.CUG.GAG etc., which reads
thr-ser-asn-thr-val-lys-leu-glu-etc. This interpretation agrees with
that for hemoglobin Constant Spring (141850.0001), which appears to be a
change in the first nucleotide of the terminator codon so that the above
sequence becomes ACX.UCX.AAA.UAC.CGU.CAA.GCU.GGA etc., which is read as
thr-ser-lys-tyr-arg-gln-ala-gly-etc. The mutation in Hb Wayne is in the
alpha-2 gene. See Seid-Akhavan et al. (1976) and Stamatoyannopoulos et
al. (1980). In a Canadian family of Scandinavian descent, Salkie et al.
(1992) described Hb Wayne in a mother and all of her 4 children.

.0005
HEMOGLOBIN QUONG SZE
HBA2, LEU125PRO

Goossens et al. (1982) described another nondeletion mechanism: mutation
in the 125th codon of the alpha-2 gene resulted in substitution of
proline for leucine in a region of the H helix of the alpha-globin
chain, which is critical for alpha-beta contact, resulting in impediment
to alpha-beta dimer formation, the initial step in hemoglobin tetramer
assembly. Thus, the alpha-thalassemia phenotype results from a novel
posttranslational mechanism. Goossens et al. (1982) named the mutant
Quong Sze, after the province in China where the mother of their proband
was born. Liang et al. (1991) reported a second example of this mutation
in a Chinese family in Guangxi (Quong Sze). Hb Quong Sze is a highly
unstable alpha-chain variant; because the abnormal alpha chains are
rapidly catabolized, the abnormal hemoglobin is difficult to detect in
reticulocytes. Identification was made through gene analysis.

.0006
HEMOGLOBIN EVANS
HBA2, VAL62MET

In the alpha-2 chain of hemoglobin from a Caucasian female with mild
hemolytic anemia, Wilson et al. (1989) demonstrated substitution of
methionine for valine at position 62. Dot-blot analysis of amplified DNA
using synthetic oligonucleotide probes confirmed the suspected G-to-A
mutation in the first position of codon 62; GTG was changed to ATG.

.0007
HEMOGLOBIN SUAN-DOK
HBA2, LEU109ARG

See Sanguansermsri et al. (1979). Hb Suan-Dok has an
alpha-thalassemia-like effect due to low production and instability of
the altered alpha-globin chain. Since the mutation (CTG to CGG) creates
a new SmaI restriction site, Hundrieser et al. (1990) diagnosed the
mutation by restriction analysis. Furthermore, they confirmed location
of the mutation in the HBA2 gene. The hemoglobin was identified in a
family from the province of Lampang in Northern Thailand. Weiss et al.
(1990) concluded that the thalassemia associated with the Suan-Dok
mutation results from instability of the mutant alpha-globin.

Regtuijt et al. (2004) described Hb Suan-Dok in a 58-year-old black
female from Curacao (West Indies) with persistent microcytic hypochromic
anemia.

.0008
HEMOGLOBIN J (BUDA)
ERYTHROCYTOSIS
HBA2, LYS61ASN

Hb J (Buda) and Hb G (Pest) (141800.0041), both alpha-chain mutants,
occurred together in a Hungarian male with erythrocytosis. The
occurrence of some normal Hb A in this man showed the existence of at
least 2 alpha loci. See Hollan et al. (1972) and Brimhall et al. (1974).
By selectively amplifying the alpha-1 and alpha-2-globin cDNAs and
hybridizing them to allele-specific oligonucleotides, Mamalaki et al.
(1990) demonstrated that the J-Buda variant has a change in the alpha-2
gene, namely, a change from AAG to AAC in codon 61.

.0009
HEMOGLOBIN SPANISH TOWN
HBA2, GLU27VAL

See Ahern et al. (1976). Cash et al. (1989) demonstrated that the
Spanish Town mutation is located in the HBA2 gene.

.0010
HEMOGLOBIN J (OXFORD)
HEMOGLOBIN I (INTERLAKEN);;
HEMOGLOBIN N (COSENZA)
HBA2, GLY15ASP

See Liddell et al. (1964), Marti et al. (1964), Silvestroni et al.
(1967), and Harano et al. (1984). This is a mutation of the HBA2 gene
(Cash et al., 1989).

.0011
HEMOGLOBIN I
HEMOGLOBIN I (BURLINGTON);;
HEMOGLOBIN I (PHILADELPHIA);;
HEMOGLOBIN I (SKAMANIA);;
HEMOGLOBIN I (TEXAS)
HBA2, LYS16GLU

The hemoglobin I mutation is curious in that it is encoded at both the
HBA1 locus (see 141800.0055) and at the HBA2 locus (Liebhaber et al.,
1984). This is presumably an example of gene conversion.

.0012
HEMOGLOBIN L (FERRARA)
HEMOGLOBIN HASHARON;;
HEMOGLOBIN SINAI;;
HEMOGLOBIN SEALY
HBA2, ASP47HIS

See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et
al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et
al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al.
(1978). The family in which hemoglobin Sealy was found was Ashkenazi
(Schneider et al., 1968). (Hemoglobin Beilinson was also found in an
Ashkenazi Jewish family and has a substitution of glycine for aspartic
acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the
HBA2 gene (Cash et al., 1989).

.0013
HEMOGLOBIN MONTGOMERY
HEMOGLOBIN BIRMINGHAM (USA)
HBA2, LEU48ARG

See Brimhall et al. (1975), Huisman et al. (1980), and Mrad et al.
(1988). The designation of this hemoglobin was changed to Hb Montgomery
when it was discovered that Hb Birmingham had already been used for an
alpha variant hemoglobin from Birmingham, England (Hb J Birmingham)
(Schneider, 1974). This is a mutation of the HBA2 gene (Cash et al.,
1989).

.0014
HEMOGLOBIN G (BRISTOL)
HEMOGLOBIN D (BALTIMORE);;
HEMOGLOBIN D (ST. LOUIS);;
HEMOGLOBIN D (WASHINGTON);;
HEMOGLOBIN G (AZAKUOLI);;
HEMOGLOBIN G (KNOXVILLE);;
HEMOGLOBIN G (PHILADELPHIA);;
HEMOGLOBIN KNOXVILLE-1;;
HEMOGLOBIN STANLEYVILLE-I
HBA2, ASN68LYS

See Dherte et al. (1959), Atwater et al. (1960), Raper et al. (1960),
Baglioni and Ingram (1961), Gammack et al. (1961), Huehns and Shooter
(1961), McCurdy et al. (1961), Minnich et al. (1962), Weatherall et al.
(1962), Dance et al. (1964), Chernoff and Pettit (1965), Schroeder and
Jones (1965), Sancar et al. (1980), Surrey et al. (1980), Brudzdinski et
al. (1984), and Morle et al. (1984). This is a mutation of the HBA2 gene
(Cash et al., 1989).

.0015
HEMOGLOBIN INKSTER
HBA2, ASP85VAL

See Reed et al. (1974). This is a mutation of the HBA2 gene (Cash et
al., 1989).

Aguinaga et al. (2000) found the same hemoglobin variant in a nonsmoking
49-year-old Caucasian male who presented with polycythemia. The authors
stated that this was the first report of Hb Inkster associated with
polycythemia in a patient with an otherwise unexplained erythrocytosis.

(Polycythemia, erythrocytosis, and erythemia are synonyms meaning
increased red blood cell mass. Authors use the terms interchangeably,
although erythemia is now almost obsolete.)

.0016
HEMOGLOBIN COLUMBIA MISSOURI
HBA2, ALA88VAL

In a 22-year-old white man who was undergoing assessment for
erythrocytosis, Perry et al. (1991) found a hemoglobin variant resulting
from substitution of valine for alanine-88 in the alpha-2 chain.

.0017
HEMOGLOBIN SUN PRAIRIE
HBA2, ALA130PRO

Harkness et al. (1990) and Plaseska et al. (1990) identified this
variant hemoglobin in an Asiatic Indian child and an Asiatic Indian
adult, respectively. The child was apparently homozygous for a G-to-C
mutation in codon 130 of the alpha-2-globin gene resulting in marked
microcytosis and hypochromia. The patient reported by Plaseska et al.
(1990) was heterozygous. The change at codon 130 was GCT-to-CCT.

Ho et al. (1996) found Hb Sun Prairie in an Asian-Indian family in which
2 daughters were homozygous for this unstable alpha-2-globin variant.
They showed chronic hemolysis, whereas the heterozygous parents were
asymptomatic with a thalassemia carrier phenotype, distinct from the
chronic hemolytic state previously described in a heterozygote. Unlike
the earlier cases in which family studies were not available, this
family clearly exhibited autosomal recessive inheritance, unusual among
variants within the same region of helix H. Globin chain biosynthesis
ratios initially suggested a beta-thalassemic hemoglobinopathy; this was
excluded by normal sequence analysis of both beta-globin genes.

Sarkar et al. (2005) studied the effects of coinheritance of the Hb Sun
Prairie mutation with a point mutation in the 5-prime UTR on the same
HBA2 chromosome in both heterozygous and homozygous states in the
eastern Indian population. Depression of translation because of the
second mutation of a conserved base in the 5-prime UTR was thought to
account for clinical severity.

.0018
HEMOGLOBIN BOYLE HEIGHTS
HBA2, ASP6DEL

See Johnson et al. (1981, 1983). Hb Boyle Heights was originally
observed in an adult Mexican male. Zhao et al. (1990) observed it in a
Caucasian family living in South Carolina. They demonstrated that the
mutation is in the major alpha-globin gene, Hb A(2).

.0019
HEMOGLOBIN DAVENPORT
HBA2, ASN78HIS

Wilson et al. (1990) found a new, stable alpha-chain variant in 2
members of a Caucasian family living in Iowa. Hematologic data were
within normal limits. The hemoglobin moved between Hb A and Hb F in
isoelectric focusing (IEF) and eluted slightly faster than Hb A2 in
cation exchange HPLC. The family was of German descent. Replacement of
asparagine by histidine at position 78 was identified.

.0020
ALPHA-THALASSEMIA
HBA2, MET1THR

Pirastu et al. (1984) demonstrated that a nondeletion form of
alpha-thalassemia was due to an initiation codon mutation (AUG to ACG)
changing methionine to threonine.

Ayala et al. (1996) studied 10 Spanish families with nondeletional
alpha-thalassemia. In 9, they identified a 5-bp deletion at the donor
site of IVS1; in 1 case, they identified the ATG-to-ACG transition in
the initiation codon.

.0021
ALPHA-THALASSEMIA
HBA2, GLU116TER

In an American black woman with alpha-thalassemia, Liebhaber et al.
(1987) demonstrated a premature termination mutation at codon 116 (GAG
to UAG) changing a glu residue to 'stop.'

.0022
HEMOGLOBIN H DISEASE, NONDELETIONAL
HBA2, MET1VAL

In a family ascertained on the basis of hemoglobin H disease (613978),
Olivieri et al. (1987) found a new nondeletion form of alpha-thalassemia
mutation, an A-to-G substitution in the initiation codon of the HBA2
gene that changed methionine to valine. This mutation abolished an NcoI
restriction site and was therefore detectable in genomic DNA by Southern
blot analysis.

.0023
HEMOGLOBIN HANAMAKI
HBA2, LYS139GLU

In a 56-year-old Japanese female who by HPLC appeared to have an
abnormally high level of Hb A(1c), Orisaka et al. (1992) found a
lys139-to-glu mutation. The mother and 1 of 3 brothers also had the
abnormal hemoglobin. The mutation in Hb Tokoname (141800.0149) resides
in the same codon. The oxygen affinity properties of the 2 hemoglobins
are similar. A second case of Hb Hanamaki was described by Rahbar et al.
(1994) in an American family with erythrocytosis.

.0024
ALPHA-THALASSEMIA-2, NONDELETIONAL
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, 3-UNT, A-G, +4

In a large family from southern Turkey, Yuregir et al. (1992) observed
nondeletional alpha-thalassemia-2 resulting from an A-to-G mutation at
nucleotide 4 in the polyadenylation signal of the HBA2 gene: AATAAA to
AATGAA. The same A-to-G replacement was present in the alpha-1
pseudogene. The mutation must cause a considerable alpha-chain
deficiency as evidenced by the hematologic data in 5 members of a family
with Hb H disease (613978) due to compound heterozygosity for
alpha-thalassemia-1 and the newly discovered poly(A) mutation.

.0025
HEMOGLOBIN KURDISTAN
HBA2, ASP47TYR

Giordano et al. (1994) reported a new alpha chain variant (Hb Kurdistan)
in a 15-year-old Kurdish refugee girl and her family from Amdea, Iraq.
Amplification and DNA analysis of both alpha genes indicated an
asp-to-tyr substitution (GAC-to-TAC) at position 47 of the HBA2 gene.
Replacement with the larger aromatic side chain of tyrosine at this
position does not induce any significant instability in the hemoglobin
molecule. In the proband's brother, this variant was associated with a
beta-thalassemia nonsense mutation at codon 39.

.0026
HEMOGLOBIN AGRINIO
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, LEU29PRO

Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of
Greek origin with an atypical form of Hb H disease (613978)
characterized by a severe hypochromic, microcytic anemia. Hall et al.
(1993) indicated that the mutation consisted of a T-to-C transition in
codon 29 of the HBA2 gene causing a leucine-to-proline transition.
Although each affected individual was a compound heterozygote for Hb
Agrinio and a previously described mutation affecting the poly(A)
addition signal of the HBB gene (141900.0383), simple heterozygotes for
the leu29-to-pro mutation have the phenotype of the alpha-thalassemia
trait.

Traeger-Synodinos et al. (1998) reported the first case of homozygosity
for Hb Agrinio. The leu29-to-pro amino acid substitution in
alpha-2-globin was caused by a CTG-to-CCG transition. The 12-month-old
Greek proband presented with marked hypochromic microcytic anemia, a
very low level of Hb H, rare Hb H inclusions, and a balanced
alpha/non-alpha biosynthesis ratio. At the age of 13 years, the proband
had a clinical phenotype compatible with mild thalassemia intermedia
with moderate anemia (Hb = 7-8 g/dL), normal growth and development,
slight splenomegaly, and minimal bone changes, while Hb H and inclusion
bodies were not detected.

.0027
HEMOGLOBIN PAKSE
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, TER142TYR

In a Laotian girl with hemoglobin H disease (613978), Waye et al. (1994)
found a TAA-to-TAT mutation converting the termination codon to a
tyrosine residue. The mutation gave rise to an elongated mRNA that would
code for an alpha-globin chain of 172 amino acid residues instead of the
normal 141 residues. The proband's father also carried the mutation. The
proband was a compound heterozygote for the Southeast Asian
alpha-thalassemia-1 deletion and the novel termination codon mutation.
Four previous mutations involving the termination codon of the
alpha-2-globin gene had been reported: Hb Constant Spring (141850.0001);
Hb Icaria (141850.0002); Hb Koya Dora (141850.0003); and Hb Seal Rock
(141850.0028).

.0028
HEMOGLOBIN SEAL ROCK
HBA2, TER142GLU

Hemoglobin Seal Rock carries a TAA-to-GAA mutation that converts the
termination codon of the HBA2 gene to glu (Bradley et al., 1975; Bunn
and Forget, 1986). Like 4 other mutations in the termination codon of
the HBA2 gene, the mutant allele codes for an alpha-chain variant of 172
amino acid residues that result in unstable elongated mRNA molecules.

.0029
HEMOGLOBIN ANAMOSA
HBA2, ALA111VAL

So-called 'silent' hemoglobin variants are characterized by the
replacement of an amino acid with one having a similar charge. These are
usually detected by separations in isoelectric focusing or HPLC because
of differences in hydrophobicity. The substitution occasionally may
affect the function of physicochemical properties of the variant to
determine the clinical or hematologic condition of its carrier. Kazanetz
et al. (1995) identified an ala111-to-val substitution in the core
peptide of HBA2 due to a change from GCC to GTC. The variant was
discovered in a Caucasian baby born in the Anamosa Community Hospital in
Anamosa, Iowa, and in his father. Stability tests on all red cell
lysates gave negative results, indicating stability of the variant
hemoglobin.

.0030
HEMOGLOBIN BIBBA
HBA2, LEU136PRO

In a large Caucasian family, Prchal et al. (1995) found that members
with congenital Heinz body hemolytic anemia were carriers of Hb Bibba.
Instability of the variant complicated isolation of the protein from
shipped blood samples. The mutation at codon 136 of the alpha-2 gene
resulted in a change from CTG to CCG and a leu136-to-pro substitution.
The first Hb Bibba heterozygote, characterized in 1968 by Kleihauer et
al. (1968), was believed to be a member of this family. The clinical
expression of the disease was surprisingly variable in severity.
Affected persons in 4 generations of the Alabama family had been
observed. (Please note that the mutation here is located in the HBA2
gene rather than in the HBA1 gene, as previously indicated in
141800.0011.)

.0031
HEMOGLOBIN SALLANCHES
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, CYS104TYR

Morle et al. (1995) found homozygosity for a mutation in the HBA2 gene
resulting in hemolytic anemia associated with a low level of hemoglobin
H. The mutation was a TGC-to-TAC transition involving codon 104 and
resulting in replacement of a cysteine by tyrosine. In vitro and in vivo
biosynthetic studies suggested that the mechanism leading to Hb H
disease (613978) in this homozygous patient was related mostly to a
significant instability of the dimers between normal beta chains and
variant alpha chains.

Khan et al. (2000) identified Hb Sallanches in a Pakistani family having
3 homozygous patients with transfusion-dependent Hb H disease. The 2
previous reports had been of a French patient and a West Indian patient.
The Pakistani cases were thought to have originated as an independent
mutation.

.0032
ALPHA-THALASSEMIA TRAIT
HBA2, 9-BP DEL/8-BP INS

Efstratiadis et al. (1980) suggested that slipped strand mispairing
(SSM) is enhanced by short (2 to 8) direct repeats, which may induce
short deletions in mammalian DNA. SSM was later suggested to play an
important in the expansion of trinucleotide repeats, causing
neurodegenerative disorders such as spinocerebellar ataxia and
Huntington disease. In addition, the size variation of microsatellite
repeats, such as polymorphic markers, is also thought to result from
SSM. SSM probably also leads to the variability in microsatellite
repeats seen in tumor cells, reflecting the high degree of genomic
instability in those tissues. Thus, SSM appears to be occur both in
germline and in somatic cells. Slippage of the replication fork is not
in itself sufficient to explain the more complex mutations in which
small deletions are combined with insertions. Oron-Karni et al. (1997)
described a deletion/duplication mutation in the HBA2 gene that allowed
them to formulate a novel mechanism accounting for the generation of
this mutation, as well as a number of other human mutations. They found
a deletion of 9 bp (codons 39 to 41), which was replaced by a nucleotide
insertion, duplicating the adjacent downstream sequence. They proposed
that the mutation arose by SSM, creating a single-stranded loop,
followed by DNA elongation, strand breathing, and the formation of a
mismatch bubble. They found in the literature 6 additional
deletion/insertion mutations in humans in which the inserted nucleotides
came from the same DNA strand. Their model explained all 6 mutations,
suggesting that rearrangement of a mismatch loop or bubble during DNA
replication may be not uncommon. The patients in whom they made their
initial observations were 2 unrelated individuals of Yemenite-Jewish
origin, referred for evaluation of unexplained mild microcytic anemia.
The hematologic data were compatible with alpha-thalassemia trait.
Because of the rarity of the mutation and the fact that it had been
found only in the 2 individuals of Yemenite-Jewish origin, The subjects
may have had a common ancestor.

.0033
HEMOGLOBIN NATAL
HBA2, TYR140TER

See Jogessar et al. (1988). This variant resulted from a TAC
(tyr)-to-TAA (stop) transversion in codon 140 of the alpha-globin gene.

.0034
HEMOGLOBIN WATTS
HBA2, 3-BP DEL, ASP74DEL OR ASP75DEL

Rahbar et al. (1997) described the first example of a trinucleotide
deletion in the HBA2 gene. In a Mexican-American family, they found that
a slightly unstable alpha-chain hemoglobin variant was due to deletion
of an aspartic acid residue through the deletion of GAC at codon 74 or
codon 75 of the HBA2 gene.

.0035
HEMOGLOBIN CONAKRY
HBA2, LEU80VAL

Cohen-Solal et al. (1998) studied a Guinean woman who was heterozygous
for hemoglobin S and had episodes of marked anemia, repeated typical
metaphyseal painful crises, and hemosiderosis. Her sickling syndrome
resulted from the association of Hb S trait with a severe pyruvate
kinase (PK) deficiency (266200) leading to a 2,3-diphosphoglycerate
(DPG) concentration of twice normal. Sequencing of the PKLR gene
revealed a previously undescribed mutation within exon 5: a 2670C-A
transversion, leading to a ser130-to-tyr amino acid substitution
(609712.0010), which the authors referred to as 'PK Conakry.' In
addition, the patient carried a new hemoglobin variant, leu80 to val,
referred to as 'Hb Conakry,' which seemed to have a mild effect. The
high intraerythrocytic 2,3-DPG concentration induced by the PK
deficiency resulted in a decreased oxygen affinity which favored
sickling to a level almost similar to that of S/C compound heterozygous
patients.

.0036
HEMOGLOBIN J (SARDEGNA)
HBA2, HIS50ASP

See Tangheroni et al. (1968) and Manca and Masala (1989).

Paleari et al. (1999) provided molecular characterization of hemoglobin
J (Sardegna), which is particularly widespread in northern Sardinia.
They characterized the variant at the DNA level as a change of codon 50
of the HBA2 gene from CAC to AAC, predicting a his-to-asn substitution.
Protein analysis, however, showed a his-to-asp substitution in the same
position. A possible explanation for these findings is that a C-to-A
mutation caused the substitution of his for asn, and that the new asn
residue subsequently underwent a posttranslational partial deamidation
to asp. Indeed, Paleari et al. (1999) identified both the asp and the
asn forms of Hb J (Sardegna).

In addition to J (Sardegna), 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 (Singapore)
(141800.0075), Hb La Roche-sur-Yon (141900.0482), Hb Osler
(141900.0211), Hb Providence (141900.0227), Hb Redondo (141900.0404),
and Hb Wayne (141850.0004).

.0037
HEMOGLOBIN TARRANT
HBA2, ASP126ASN

Perea et al. (1999) provided the molecular characterization of a
hemoglobin variant in a Mexican family. Located in the HBA2 gene, an
asp126-to-asn amino acid substitution resulted in a variant with high
oxygen affinity. Previously described in 4 families with Mexican
ancestors, the variant was known as Hb Tarrant (Moo-Penn et al., 1977).

.0038
HEMOGLOBIN ANTANANARIVO
HBA2, VAL1GLY

During a systematic hematologic study, Kister et al. (1999) identified a
val1-to-gly mutation in the HBA2 gene in a 24-year-old woman who came
from Madagascar. The mutation is a clinically silent variant in which
the structural modification disturbs the oxygen-linked chloride binding.

.0039
HEMOGLOBIN BOGHE
HBA2, HIS58GLN

Lacan et al. (1999) found Hb Boghe in a 12-month-old girl who was
treated for malignant histiocytosis at 9 months of age and received a
bone marrow transplant from her sister. Hb Boghe was undetectable by
isoelectrofocusing and high performance liquid chromatography of
hemoglobins. It was only revealed by polyacrylamide gel electrophoresis
of globin chains in the presence of urea-Triton X-100 and accounted for
10% of the total hemoglobin. The amino acid change resulted from a
CAC-to-CAA mutation in codon 58.

.0040
HEMOGLOBIN TOULON
HBA2, PRO77HIS

In 2 apparently unrelated diabetic women living in different parts of
France, Badens et al. (1999) found a hemoglobin variant during
chromatographic measurement of glycated Hb. Codon 77 of the HBA2 gene
was found to be changed from CCC (pro) to CAC (his).

Waye et al. (2000) reported a second instance of Hb Toulon in a Canadian
family of Italian descent.

Caruso et al. (2002) described what they referred to as the first
Italian case of Hb Toulon.

.0041
HEMOGLOBIN CAMPINAS
HBA2, ALA26VAL

Wenning et al. (2000) identified an electrophoretically silent
hemoglobin variant in a healthy 9-year-old Caucasian Brazilian boy and
his mother. The variant, which the authors called Hb Campinas, was a
single base substitution at codon 26 of the alpha-2 globin gene: GCG
(ala) to GTG (val).

.0042
HEMOGLOBIN NIKAIA
HBA2, HIS20ASP

Prehu et al. (2000) identified Hb Nikaia, a CAC-to-GAC change in the
HBA2 gene resulting in a his20-to-asp substitution, in a 50-year-old
French Caucasian man during measurement of glycated hemoglobin. The name
of the variant was derived from the ancient Greek name of the city of
Nice.

.0043
HEMOGLOBIN CLINICO-MADRID
HBA2, LYS90ARG

In a newborn in Madrid, Spain, Villegas et al. (2000) found an A-to-G
transition in exon 2 of the HBA2 gene, changing codon 90 from AAG (lys)
to AGG (arg).

.0044
HEMOGLOBIN CLINICO-MADRID
HEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
HBA2, IVS2AS, G-A, -1

In an Argentinian patient with Hb H disease (613978) and her daughter,
Noguera et al. (2001) found a splice acceptor consensus point mutation
changing AG to AA in intron 2. Their patient was of Arab and Italian
ancestry. The phenotypic expression observed in the heterozygote, namely
microcytic erythrocytes, slightly hypochromic, was rather more severe
than in individuals with a deleted gene. This observation was thought to
be in accord with the fact that the mutation affects HBA2, whose level
of expression is 3 times higher than that of the HBA1 gene.

.0045
HEMOGLOBIN DARTMOUTH
HBA2, LEU66PRO

McBride et al. (2001) reported a mutation in monozygotic twins and
designated it Hb Dartmouth, after the medical center at which the
patients were cared for. The mother, of Khmer ancestry, was heterozygous
for alpha-thalassemia-1 due to deletion of both HBA1 and HBA2, common in
Southeast Asians. The father, of Scottish-Irish ancestry, was a silent
carrier of a leu66-to-pro mutation of the HBA2 gene. The twins had
severe neonatal anemia requiring transfusion and were compound
heterozygotes for the 2 mutations.

.0046
HEMOGLOBIN GERLAND
HBA2, VAL55ALA

In studies of a 6-year-old boy with mild microcytic anemia, Lacan et al.
(2001) found a neutral alpha-chain variant involving the HBA2 gene and
designated it Hb Gerland. A GTT-to-GCT mutation of codon 55 was
predicted to result in a substitution of alanine for valine.

.0047
HEMOGLOBIN MANITOBA
HBA2, SER102ARG

Hb Manitoba (ser102 to arg) was discovered in a Canadian family by
Crookston et al. (1970) and was subsequently found in an Italian patient
by Sciarratta et al. (1984). Chang et al. (2001) observed the same
variant for the first time in an Asian family in Taiwan.

.0048
HEMOGLOBIN PARK RIDGE
HBA2, ASN9LYS

In an apparently well, 6-month-old Caucasian child, Hoyer et al. (2002)
found an AAC-to-AAG transversion in codon 9 of the HBA2 gene resulting
in an asn9-to-lys (N9K) change. Hb Delfzicht (141800.0208) has the same
mutation in the HBA1 gene.

.0049
HEMOGLOBIN NORTON
HBA2, HIS72ASP

In a 7-month-old Caucasian child who was apparently well and
hematologically normal, Hoyer et al. (2002) found a his72-to-asp
mutation in the alpha-2 chain. Three other alpha-chain variants had been
reported at this site with no apparent abnormality: Hb Gouda
(141800.0198), Hb Fuchu-I (141800.0196), and Hb Daneshgah-Tehran
(141800.0026). Hoyer et al. (2002) stated that 4 previously reported
beta chain variants with substitution of his77 in the beta-globin chain
likewise appeared to be without hematologic effect.

.0050
HEMOGLOBIN LOMBARD
HBA2, HIS103TYR

In a 34-year-old male of Italian (Calabrian) ancestry who was clinically
well and without hematologic abnormality, Hoyer et al. (2002) described
a CAC-to-TAC transition in codon 103 of the HBA2 gene, resulting in a
his103-to-tyr substitution. The same mutation had been reported in the
HBA1 gene as Hb Charolles (141800.0203) in a person of Sardinian origin,
who also had microcytosis that may have been due to mutation of the
3-prime polyadenylation site of the HBA2 gene.

.0051
HEMOGLOBIN SAN ANTONIO
HBA2, LEU113ARG

In a 1-year-old Caucasian male who was asymptomatic and hematologically
normal, Hoyer et al. (2002) found a CTC-to-CGC transversion in codon 113
of the HBA2 gene resulting in a leu113-to-arg (L113R) change.

.0052
HEMOGLOBIN RAMPA
HBA2, PRO95SER

Hb Rampa, a pro95-to-ser (P95S) change in the HBA2 gene, was first
described in a few members of the Koya Dora tribe of Andhra Pradesh,
India (De Jong et al., 1971). Additional cases were reported in a person
of north European origin (Smith et al., 1972) and a French-Canadian
family (Huisman et al., 1978). Hoyer et al. (2002) described Hb Rampa in
a 53-year-old asymptomatic male of German ancestry living in the United
States.

.0053
HEMOGLOBIN MANAWATU
HBA2, PRO37LEU

Brennan et al. (2002) described Hb Manawatu, a pro37-to-leu (P37L)
variant of the HBA2 gene, in a 28-year-old female of British descent
living in New Zealand who was heterozygous for a CCC-to-CTC transition.
The authors stated that the only other recorded mutation at position
alpha-37(C2) was Hb Bourmedes, a pro37-to-arg (P37R; 141800.0012) change
in the HBA1 gene.

.0054
HEMOGLOBIN G (HONOLULU)
HEMOGLOBIN G (HONG KONG);;
HEMOGLOBIN G (SINGAPORE);;
HEMOGLOBIN G (CHINESE)
HBA2, GLU30GLN

See Schneider and Jim (1961), Lehmann (1962), Swenson et al. (1962), and
Lie-Injo et al. (1979). The original Hb G (Chinese) variant was thought
to have a beta-chain substitution (Gammack et al., 1961).

Chang et al. (2002) observed this variant in a Taiwanese family and
found that it was caused by a G-to-C substitution at the first base of
codon 30 (GAG-to-CAG) of the HBA2 gene, resulting in the substitution of
a glutamic acid residue by glutamine (E30Q). The mutation created a PstI
restriction site and abolished an authentic BstNI site.

Shih et al. (2003) identified Hb G (Chinese) with alpha-thalassemia-1 of
the Thai type in a Taiwanese family.

.0055
HEMOGLOBIN PRATO
HBA2, ARG31SER

Marinucci et al. (1979) described this hemoglobin variant in a family of
Sicilian origin living in Prato (near Florence in northern Italy). De
Marco et al. (1992) found Hb Prato in a Calabrian family. The
replacement of the arginine residue by serine occurs at position 31
(arg31 to ser; R31S) of the alpha-2-globin chain. Shih et al. (2003)
observed this variant in a Taiwanese individual who was a compound
heterozygote for Hb Prato and alpha-thalassemia.

.0056
ALPHA-THALASSEMIA, DUTCH TYPE
HBA2, IVS1, A-G, -116

Harteveld et al. (1996) described an IVS1-116A-G acceptor splice site
mutation in the HBA2 gene, causing a very mild alpha(+)-thalassemia
phenotype, in 2 Dutch families.

Harteveld et al. (2003) reported a third independent case of this
alpha-thalassemia point mutation in a healthy 23-year-old Dutch woman;
this was the first case defining the phenotype in combination with a
frequent alpha(+)-thalassemia deletion defect.

.0057
ALPHA-THALASSEMIA, ZF TYPE
HBA2, METHYLATION SILENCING DUE TO ANTISENSE TRANSCRIPT

Barbour et al. (2000) reported an individual (called ZF) with
alpha-thalassemia due to a unique deletion (called alpha(-)-ZF) that
removed the HBA1 gene (141800) and the HBQ1 gene (142240) and juxtaposed
a region that normally lies approximately 18 kb downstream of the
alpha-globin cluster to a site next to the structurally normal HBA2
gene. The alpha(-)-ZF deletion did not remove any positive cis-acting
sequences, but expression of the structurally intact alpha-globin gene
was stably silenced and, during development, its CpG island became
densely methylated and insensitive to endonucleases over a region of
approximately 2 kb. Tufarelli et al. (2003) showed that the deletion had
truncated the widely expressed gene LUC7L (607782), which is transcribed
from the opposite DNA strand. They showed that in the affected
individual, in a transgenic model, and in differentiating embryonic stem
cells, transcription of antisense RNA mediated silencing and methylation
of the associated CpG island. This was identified as a novel mechanism
underlying human genetic disease.

.0058
HEMOGLOBIN CHARTRES
HBA2, PHE33SER

Prehu et al. (2003) found a new phe33-to-ser (F33S) variant (designated
Hb Chartres) in the HBA2 gene in a 31-year-old female of French origin
presenting with mild microcytic hypochromic anemia. No family studies
could be performed.

.0059
HEMOGLOBIN FUKUI
HBA2, LYS139ASN

Harano et al. (2003) found a lys139-to-asn (K139N) missense mutation,
resulting from an AAA-to-AAC transversion, in a 52-year-old Japanese
male. The change was in the same position 139 of the alpha-2 chain as
hemoglobin Tokoname (K139T; 141800.0149) and Hb Hanamaki (K139E;
141850.0023), 2 variants found in Japanese, both of which show high
oxygen affinity. Harano et al. (2003) found that the nucleotide sequence
of Hb Tokoname was ACA instead of AAA at codon 139 of the alpha-2-globin
gene. In the case of Hb Hanamaki, 9 of 12 Japanese families found
Honshu, the main island of Japan, were investigated, and the nucleotide
sequence GAA instead of AAA was identified at codon 139 of the
alpha-1-globin gene. However, in 1 family found in Kyushu, the western
most main island, the mutation was identified in the alpha-2-globin
gene. Thus, 3 different types of mutation at the same codon of the
alpha-globin gene were discovered in the same population and, moreover,
in the case of Hb Hanamaki, the nucleotide mutation was observed in both
the alpha-1- and the alpha-2-globin genes.

.0060
HEMOGLOBIN PART-DIEU
HBA2, ALA65THR

In a 58-year-old man of French Caucasian origin living in Lyon, France,
Lacan et al. (2004) identified an ala65-to-thr (A65T) mutation in the
HBA2 gene. The patient suffered from type II diabetes (125853) and had
hepatomegaly, splenomegaly, microlithiasis, hypercholesterolemia, and
hypertriglyceridemia.

.0061
HEMOGLOBIN DECINES-CHARPIEU
HBA2, ALA69THR

In a 34-year-old man of French Caucasian origin living in the city of
Decines-Charpieu in the south of France, Lacan et al. (2004) identified
an ala69-to-thr (A69T) mutation in the HBA2 gene.

.0062
HEMOGLOBIN VAL DE MARNE
HEMOGLOBIN FOOTSCRAY
HBA2, SER133ARG

Two different research teams, Wajcman et al. (1993) and Owen and Hendy
(1994), independently reported this hemoglobin variant, a ser133-to-arg
(S133R) substitution. Wajcman et al. (1993) discovered the mutation
(named Hb Val de Marne) in 2 French newborns who were first cousins.
Owen and Hendy (1994) found the hemoglobin variant (named Hb Footscray)
in a 27-year-old male of Polish-Hungarian descent. Position 133 is an
internal residue located near the heme pocket and the C-terminal end of
the alpha subunit. The mutation from serine to arginine at this position
may facilitate the access of oxygen, or water, to the heme iron. When
compared to adult hemoglobin (Hb A), the variant hemoglobin's oxygen
affinity is increased 1.7-fold and the autooxidation rate is slightly
increased.

Ma et al. (2004) demonstrated that the S133R mutation, caused by an
AGC-to-AGA transversion, is due to mutation in the HBA2 gene and not in
the HBA1 gene. They found the variant in a 15-year-old Chinese girl and
her father.

.0063
ALPHA-THALASSEMIA
HBA2, GLU23TER

Siala et al. (2004) described a 3-year-old Tunisian girl who had Hb
Bart's (gamma-4) at birth, later on presenting with moderate anemia,
microcytosis, and hypochromia; she had a normal HBA2 level and no
abnormal hemoglobin fraction. After excluding most of the common
Mediterranean mutations, sequencing of the HBA2 gene identified a
heterozygous change of codon 23 from GAG (glu) to TAG (ter) (glu23 to
ter). The E23X mutation was also found in the mother in heterozygous
state.

.0064
ALPHA-PLUS-THALASSEMIA
HBA2, GLY22GLY

In a 79-year-old woman of Surinamese-Hindustani origin with moderate
microcytic hypochromic anemia, Harteveld et al. (2004) identified a
silent mutation at codon 22 of the HBA2 gene, GGC (gly) to GGT (gly)
(gly22 to gly), resulting in a splice donor site consensus sequence
between codons 22 and 23. The abnormally spliced mRNA led to a premature
termination between codons 48 and 49. The presence of a downstream
intron was thought to induce the intracellular degradation of the
affected mRNA, through the pathway of nonsense-mediated decay (NMD),
thus explaining the alpha(+)-thalassemia phenotype of the patient. The
C-to-T transition was said to be the first reported mutation creating a
splice donor site in 1 of the alpha-globin genes.

.0065
HEMOGLOBIN ZURICH ALBISRIEDEN
ALPHA-PLUS-THALASSEMIA, INCLUDED
HBA2, GLY59ARG

In a patient presenting with persistent hypochromic microcytosis and
erythrocytosis, Dutly et al. (2004) identified a G-to-C transversion in
the HBA2 gene, resulting in a gly59-to-arg (G59R) substitution. The
defect, designated Hb Zurich Albisrieden, was not detected at the
protein level and led to alpha-plus-thalassemia.

.0066
HEMOGLOBIN PASSY
HBA2, SER81PRO

In a 3-month-old Turkish boy investigated for anemia with hypochromia
and microcytosis, Lacan et al. (2005) identified a TCC-to-CCC transition
in codon 81 of the HBA2 gene, resulting in substitution of proline for
serine (S81P).

.0067
HEMOGLOBIN PLASENCIA
HBA2, LEU125ARG

In a Spanish family residing in Plasencia with moderate microcytosis and
hypochromia, Martin et al. (2005) identified heterozygosity for a
CTG-to-CGG transversion at codon 125 of the HBA2 gene, resulting in a
leu125-to-arg substitution.

.0068
HEMOGLOBIN KUROSAKI
HBA2, LYS7GLU

In the course of assaying glycosylated hemoglobin in a diabetic patient,
Harano et al. (1995) found a new alpha-chain variant, which they named
Hb Kurosaki after the city where the patient lived. Structural analysis
demonstrated substitution of glutamic acid for lysine at position 7.
From studies of a 30-year-old Thai male with normal hematologic profile
at the steady state, Ngiwsara et al. (2005) found the same hemoglobin
variant and demonstrated that the mutation was localized to the HBA2
gene and was caused by heterozygosity for an AAG-to-GAG transition in
codon 7.

.0069
HEMOGLOBIN H DISEASE, NONDELETIONAL
HBA2, 1-BP DEL, 2T

Viprakasit et al. (2005) stated that in Thailand at least 7,000 new
cases of Hb H disease (613978) are expected each year, because nearly
25% of the population is heterozygous for either deletional or
nondeletional alpha-thalassemia determinants. The clinical phenotypes of
affected individuals with Hb H disease are highly variable, ranging from
stillbirths in Hb Bart's hydrops fetalis to very mild clinical symptoms.
Viprakasit et al. (2005) described a rare initiation codon mutation of
the HBA2 gene, a 1-bp deletion of thymine at the second nucleotide of
the ATG initiation codon, in compound heterozygous state with
alpha-0-thalassemia. Other reported changes in the initiation codon of
HBA2 are met1 to thr (141850.0020) and met1 to val (141850.0022).

This mutation was described for the first time by Waye et al. (1997) in
an 8-year-old Canadian girl of Vietnamese descent. Pallor had been
evident since birth, and hypochromic microcytic anemia was first
documented at age 20 months.

.0070
HEMOGLOBIN AL-HAMMADI RIYADH
HBA2, ASP75VAL

During a routine hemoglobin analysis for anemia in a 16-month-old boy
who lived in Riyadh, Saudi Arabia, Burnichon et al. (2006) identified
heterozygosity for an A-T transversion in exon 2 of the HBA2 gene,
resulting in an asp75-to-val (D75V) substitution. The child had no
hepatomegaly or splenomegaly. This was the sixth hemoglobin variant
described at position 75 of the alpha-globin chain.

.0071
ALPHA-THALASSEMIA, HMONG TYPE
HBA2, 1-BP DEL, 1A

Eng et al. (2006) studied a newborn male of Hmong descent who had an
elevated level of Hb Bart's (more than 25%) indicative of Hb H disease.
Deletion-specific PCR demonstrated that he was heterozygous for the
Southeast Asian alpha-0-thal deletion. PCR amplification and direct
nucleotide sequence analysis of the intact alpha-globin gene cluster
revealed a 1-bp deletion of adenine from the translation initiation
codon (ATG) of the HBA2 gene.

.0072
HEMOGLOBIN H HYDROPS FETALIS SYNDROME
HBA2, 3-BP DEL, GLU30

In a patient with hemoglobin H hydrops fetalis (see 236750), Chan et al.
(1997) detected a deletion of codon 30 (deltaGAG, glu) in the hemoglobin
alpha-2 gene on one chromosome The other chromosome carried a large
deletion that removed both alpha-globin genes and the zeta-globin
(142310) gene. The mutant protein was apparently highly unstable since
there was no detectable radioactive or protein peak upon in vitro globin
chain synthesis. HbH was 2.5%, Hb Bart's 31%, HbF 28%, and HbA 38.5%. In
a review of the literature, Lorey et al. (2001) noted that this patient
died minutes after birth at 39 weeks' gestation, with ascites,
hepatomegaly, and placentomegaly present.

.0073
HEMOGLOBIN H HYDROPS FETALIS SYNDROME
HBA2, GLY59ASP

In a patient with hemoglobin H hydrops fetalis (see 236750), Chan et al.
(1997) detected a gly59-to-asp (G59D) substitution on one allele of the
HBA2 gene, resulting from a G-to-A transition. Both alpha-globin genes
on the other chromosome were removed by the Southeast Asian deletion
(Lorey et al., 2001). Fetal blood sampling at 28 weeks' gestation
revealed Hb Bart's of 39%, HbF 39%, and HbA 9%. An intrauterine
transfusion was given at 29 weeks, and the patient was delivered by
cesarean section at 34 weeks. The baby survived a turbulent neonatal
period and was discharged at 3 months of age. He required monthly
transfusions and at age 2 years had passed normal developmental
milestones. Chan et al. (1997) noted that this same mutation had been
reported in the HBA1 gene (Hb Adana; 141800.0174) and had been
coinherited with an alpha-thalassemia-1 deletion on the other allele,
resulting in hemoglobin H disease. Chan et al. (1997) suggested that the
more severe phenotype in their patient had resulted from the missense
mutation's occurrence in the HBA2 gene, which transcribes up to twice as
much mRNA as the HBA1 gene.

.0074
HEMOGLOBIN H HYDROPS FETALIS SYNDROME
HBA2, SER35PRO

In a patient of Filipino ancestry with hemoglobin H hydrops fetalis
syndrome (see 236750), Lorey et al. (2001) detected a ser35-to-pro
(S35P) substitution in the paternal allele of the HBA2 gene that had
resulted from a T-to-C transition. The maternal chromosome carried the
Filipino deletion removing the alpha-1 (141800), alpha-2, and
zeta-globin (142310) genes. Clinical manifestations at birth by cesarean
section at 34 weeks included pericardial effusion, fetal distress,
jaundice, hepatosplenomegaly, ambiguous genitalia with fourth-degree
hypospadias, and bilateral inguinal testes. He required 6 transfusions
in the first 4 months of life; thereafter, hemoglobin levels stabilized.
At 13 months of age developmental milestones were consistent with an
estimated chronologic age of 10 months.

*FIELD* SA
Carver and Kutlar (1995); Derry et al. (1984); Higgs et al. (1983);
Lie-Injo et al. (1974); Liebhaber and Cash (1985); Milner et al. (1971);
Orkin et al. (1981)
*FIELD* RF
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69. Johnson, C. S.; Schroeder, W. A.; Shelton, J. B.; Shelton, J.
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167. Waye, J. S.; Eng, B.; Patterson, M.; Chui, D. H. K.; Olivieri,
N. F.: Identification of a novel termination codon mutation (TAA-to-TAT,
term-to-tyr) in the alpha-2-globin gene of a Laotian girl with hemoglobin
H disease. (Letter) Blood 83: 3418-3420, 1994.

168. Weatherall, D. J.; Sigler, A. T.; Baglioni, C.: Four hemoglobins
in each of three brothers: genetic and biochemical significance. Bull.
Johns Hopkins Hosp. 111: 143-156, 1962.

169. Weiss, I.; Cash, F. E.; Coleman, M. B.; Pressley, A.; Adams,
J. G.; Sanguansermsri, T.; Liebhaber, S. A.; Steinberg, M. H.: Molecular
basis for alpha-thalassemia associated with the structural mutant
hemoglobin Suan-Dok (alpha-2 109leu-to-arg). Blood 76: 2630-2636,
1990. Note: Erratum: Blood 77: 1404 only, 1991.

170. Wen, X.-J.; Liang, S.; Jin, Q.; Lin, W.-X.: The nondeletional
types of Hb H disease in Guangxi. Hemoglobin 16: 45-50, 1992.

171. Wenning, M. R. S. C.; Silva, N. M.; Jorge, S. B.; Kimura, E.
M.; Costa, F. F.; Torsoni, M. A.; Ogo, S. H.; Sonati, M. F.: Hb Campinas
(alpha-26(B7)ala-to-val): a novel, electrophoretically silent, variant. Hemoglobin 24:
143-148, 2000.

172. Whitelaw, E.; Proudfoot, N.: Alpha-thalassaemia caused by a
poly(A) site mutation reveals that transcriptional termination is
linked to 3-prime end processing in the human alpha-2 globin gene. EMBO
J. 5: 2915-2922, 1986.

173. Wilson, J. B.; Webber, B. B.; Kutlar, A.; Reese, A. L.; McKie,
V. C.; Lutcher, C. L.; Felice, A. E.; Huisman, T. H. J.: HB Evans
or alpha-2 62 (E11) val-to-met: an unstable hemoglobin causing a mild
hemolytic anemia. Hemoglobin 13: 557-566, 1989.

174. Wilson, J. B.; Webber, B. B.; Plaseska, D.; de Alarcon, P. A.;
McMillan, S. K.; Huisman, T. H. J.: Hb Davenport or alpha-2 78(EF7)
asn-to-his. Hemoglobin 14: 599-605, 1990.

175. Yuregir, G. T.; Aksoy, K.; Curuk, M. A.; Dikmen, N.; Fei, Y.-J.;
Baysal, E.; Huisman, T. H. J.: Hb H disease in a Turkish family resulting
from the interaction of a deletional alpha-thalassaemia-1 and a newly
discovered poly A mutation. Brit. J. Haemat. 80: 527-532, 1992.

176. Zhao, W.; Wilson, J. B.; Huisman, T. H. J.: Low quantities of
Hb Boyle Heights or alpha-2 6 (A4) asp-to-del observed in three members
of a Caucasian family. Hemoglobin 14: 637-640, 1990.

*FIELD* CN
Ada Hamosh - updated: 12/14/2012
Anne M. Stumpf - updated: 7/25/2011
Victor A. McKusick - updated: 9/19/2006
Victor A. McKusick - updated: 3/29/2006
Victor A. McKusick - updated: 11/1/2005
Victor A. McKusick - updated: 10/11/2005
Victor A. McKusick - updated: 8/11/2005
Victor A. McKusick - updated: 6/30/2005
Victor A. McKusick - updated: 5/11/2005
Victor A. McKusick - updated: 3/3/2005
Victor A. McKusick - updated: 12/6/2004
Victor A. McKusick - updated: 12/3/2004
Victor A. McKusick - updated: 6/2/2004
Victor A. McKusick - updated: 9/2/2003
Victor A. McKusick - updated: 5/20/2003
Victor A. McKusick - updated: 5/13/2003
Victor A. McKusick - updated: 4/17/2003
Victor A. McKusick - updated: 3/5/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 9/16/2002
Victor A. McKusick - updated: 2/27/2002
Victor A. McKusick - updated: 11/6/2001
Victor A. McKusick - updated: 2/14/2001
Victor A. McKusick - updated: 9/15/2000
Victor A. McKusick - updated: 1/21/2000
Carol A. Bocchini - updated: 12/14/1999
Victor A. McKusick - updated: 12/8/1999
Victor A. McKusick - updated: 3/25/1999
Victor A. McKusick - updated: 2/2/1999
Victor A. McKusick - updated: 9/29/1997
Moyra Smith - updated: 4/6/1996

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

*FIELD* ED
terry: 03/28/2013
alopez: 12/19/2012
terry: 12/14/2012
alopez: 7/25/2011
alopez: 5/13/2011
terry: 10/12/2010
terry: 12/16/2009
wwang: 5/4/2009
terry: 2/3/2009
terry: 1/15/2009
terry: 1/14/2009
alopez: 11/19/2008
wwang: 10/3/2006
terry: 9/19/2006
terry: 3/29/2006
wwang: 3/1/2006
carol: 11/18/2005
alopez: 11/8/2005
terry: 11/1/2005
carol: 10/27/2005
carol: 10/21/2005
wwang: 10/21/2005
terry: 10/11/2005
carol: 10/3/2005
wwang: 8/18/2005
terry: 8/11/2005
carol: 7/1/2005
terry: 6/30/2005
wwang: 6/7/2005
wwang: 5/13/2005
terry: 5/11/2005
tkritzer: 3/11/2005
terry: 3/3/2005
tkritzer: 1/25/2005
terry: 12/6/2004
terry: 12/3/2004
tkritzer: 6/8/2004
terry: 6/2/2004
tkritzer: 1/5/2004
cwells: 11/10/2003
cwells: 9/3/2003
terry: 9/2/2003
terry: 7/30/2003
terry: 7/28/2003
alopez: 6/3/2003
alopez: 5/23/2003
terry: 5/20/2003
terry: 5/13/2003
tkritzer: 5/5/2003
tkritzer: 4/30/2003
terry: 4/17/2003
carol: 3/11/2003
tkritzer: 3/7/2003
terry: 3/5/2003
terry: 3/3/2003
tkritzer: 10/7/2002
tkritzer: 10/3/2002
tkritzer: 10/2/2002
carol: 9/16/2002
cwells: 3/22/2002
cwells: 3/20/2002
terry: 2/27/2002
alopez: 11/12/2001
terry: 11/6/2001
carol: 2/19/2001
mcapotos: 2/19/2001
mcapotos: 2/16/2001
terry: 2/14/2001
mcapotos: 10/12/2000
mcapotos: 10/10/2000
carol: 9/27/2000
mcapotos: 9/27/2000
terry: 9/15/2000
carol: 2/8/2000
mcapotos: 2/7/2000
terry: 1/21/2000
mcapotos: 12/15/1999
carol: 12/14/1999
carol: 12/8/1999
terry: 12/8/1999
mgross: 8/26/1999
carol: 8/20/1999
terry: 4/30/1999
mgross: 4/2/1999
mgross: 3/30/1999
terry: 3/25/1999
carol: 2/15/1999
terry: 2/2/1999
dkim: 7/2/1998
mark: 10/3/1997
jenny: 10/1/1997
terry: 9/29/1997
alopez: 8/7/1997
alopez: 8/1/1997
alopez: 7/29/1997
jenny: 6/23/1997
terry: 6/19/1997
mark: 6/14/1997
mark: 1/10/1997
jenny: 1/7/1997
terry: 12/13/1996
terry: 12/10/1996
terry: 11/18/1996
mark: 7/22/1996
mark: 4/6/1996
mark: 1/28/1996
terry: 1/23/1996
mark: 9/17/1995
carol: 7/9/1995
terry: 6/15/1995
davew: 8/5/1994
jason: 7/29/1994
warfield: 4/8/1994

MIM 141860
*RECORD*
*FIELD* NO
141860
*FIELD* TI
*141860 HEMOGLOBIN--ALPHA LOCUS 3
;;ALPHA-GLOBIN LOCUS, THIRD
*FIELD* TX
In apes, Boyer et al. (1973) found evidence for a third alpha locus. The
read more2 alpha chains of man are identical in amino acid sequence. The same is
true for the chimpanzee, gorilla and gibbon. The orangutan alpha chains
differ by 1 amino acid. Some persons have 1 alpha locus and rare
individuals have 3. Whether those homozygous for 3 loci are at a
disadvantage is unclear. Those with 1 locus (a frequent finding in
American Blacks) have alpha-thalassemia trait when it is homozygous.
Those with 1 gene (out of the usual 4) have Hb H disease. The 2 alpha
genes are 3.7 kb apart; the 2 adult globin genes (delta and beta) are
7.0 kb apart. Presumably the closer positioning and other
characteristics of the 2 alpha genes allow readier unequal crossingover.
The beta and delta genes also have larger introns (intervening
sequences) than do the alpha genes. About 0.0036 of American Blacks and
0.05 of Greek Cypriots are heterozygous for 3 alpha loci. In a Welch
family, Higgs et al. (1980) found 3 persons with 5 alpha genes.

*FIELD* SA
Lie-Injo et al. (1981); Trent et al. (1981)
*FIELD* RF
1. Boyer, S. H.; Noyes, A. N.; Boyer, M. L.; Marr, K.: Hemoglobin
3-alpha chains in apes. J. Biol. Chem. 248: 992-1003, 1973.

2. Higgs, D. R.; Old, J. M.; Pressley, L.; Clegg, J. B.; Weatherall,
D. J.: A novel alpha-globin gene arrangement in man. Nature 284:
632-635, 1980.

3. Lie-Injo, L. E.; Herrera, A. R.; Kan, Y. W.: Two types of triplicated
alpha-globin loci in humans. Nucleic Acids Res. 9: 3707-3717, 1981.

4. Trent, R. J.; Higgs, D. R.; Clegg, J. B.; Weatherall, D. J.: A
new triplicated alpha-globin gene arrangement in man. Brit. J. Haemat. 49:
149-152, 1981.

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

*FIELD* ED
dkim: 07/02/1998
mimadm: 9/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
carol: 4/20/1989
marie: 3/26/1988

MIM 604131
*RECORD*
*FIELD* NO
604131
*FIELD* TI
#604131 ALPHA-THALASSEMIA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morealpha-thalassemia is caused by mutations in the alpha-globin genes
(HBA1, 141800; HBA2, 141850).

Sequences 30 to 50 kb upstream from the alpha-globin gene cluster,
referred to as the locus control region alpha (LCRA; 152422), have been
found to be deleted in cases of alpha-thalassemia with structurally
intact alpha-globin genes. The molecular and clinical aspects of the
severe alpha-thalassemia syndromes were reviewed by Higgs (1993) and
Chui and Waye (1998).

Weatherall (2001) reviewed phenotype-genotype relationships in monogenic
diseases based on studies of the thalassemias. The remarkable phenotypic
diversity of the beta-thalassemias reflects the heterogeneity of
mutations at the HBB locus, the action of many secondary and tertiary
modifiers, and a wide range of environmental factors. Weatherall (2001)
stated that phenotype-genotype relations will likely be equally complex
in many monogenic diseases. The findings reviewed by Weatherall (2001)
highlighted the problems that might be encountered in defining the
relationship between the genome and the environment in multifactorial
disorders, in which the degree of heritability may be relatively low and
several environmental agents are involved.

MOLECULAR GENETICS

For a review of mutations in the HBA genes causing alpha-thalassemia,
see 141800 and 141850.

*FIELD* RF
1. Chui, D. H. K.; Waye, J. S.: Hydrops fetalis caused by alpha-thalassemia:
an emerging health care problem. Blood 91: 2213-2222, 1998.

2. Higgs, D. R.: Alpha-thalassaemia. Baillieres Clin. Haemat. 6:
117-150, 1993.

3. Weatherall, D. J.: Phenotype-genotype relationships in monogenic
disease: lessons from the thalassaemias. Nature Rev. Genet. 2: 245-255,
2001.

*FIELD* CN
Victor A. McKusick - updated: 8/29/2003
Victor A. McKusick - updated: 8/9/2002

*FIELD* CD
Victor A. McKusick: 8/16/1999

*FIELD* ED
carol: 05/20/2011
carol: 6/3/2009
carol: 8/29/2003
tkritzer: 8/16/2002
tkritzer: 8/14/2002
terry: 8/9/2002
alopez: 12/6/1999
carol: 8/20/1999

MIM 613978
*RECORD*
*FIELD* NO
613978
*FIELD* TI
#613978 HEMOGLOBIN H DISEASE; HBH
;;ALPHA-THALASSEMIA, HEMOGLOBIN H TYPE;;
HEMOGLOBIN H DISEASE, DELETIONAL
read moreHEMOGLOBIN H DISEASE, NONDELETIONAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because hemoglobin H disease
is caused by contiguous gene deletion of the hemoglobin alpha-1 (HBA1;
141800) and alpha-2 (HBA2; 141850) genes on one chromosome 16, and a
defect, deletional or nondeletional, in either HBA1 or HBA2 on the
other.

DESCRIPTION

Hemoglobin H disease is a subtype of alpha-thalassemia (see 604131) in
which patients have compound heterozygosity for alpha(+)-thalassemia,
caused by deletion of one alpha-globin gene, and for
alpha(0)-thalassemia, caused by deletion in cis of 2 alpha-globin genes
(summary by Lal et al., 2011). When 3 alpha-globin genes become inactive
because of deletions with or without concomitant nondeletional
mutations, the affected individual has only 1 functional alpha-globin
gene. These people usually have moderate anemia and marked microcytosis
and hypochromia. In affected adults, there is an excess of beta-globin
chains within erythrocytes that will form beta-4 tetramers, also known
as hemoglobin H (summary by Chui et al., 2003).

Hb H disease is usually caused by the combination of
alpha(0)-thalassemia with deletional alpha(+)-thalassemia, a combination
referred to as 'deletional' Hb H disease. In a smaller proportion of
patients, Hb H disease is caused by an alpha(0)-thalassemia plus an
alpha(+)-thalassemia point mutation or small insertion/deletion. Such a
situation is labeled 'nondeletional' Hb H disease. Patients with
nondeletional Hb H disease are usually more anemic, more symptomatic,
more prone to have significant hepatosplenomegaly, and more likely to
require transfusions (summary by Lal et al., 2011).

While most thalassemia-related hydrops fetalis is caused by the lack of
all alpha-globin genes, there are reports of fetuses with Hb H disease
that developed the hydrops fetalis syndrome; see 236750.

BIOCHEMICAL FEATURES

Hemoglobin H is observed as a 'fast' electrophoretic variant. Rigas et
al. (1955), Jones et al. (1959), Kattamis and Lehmann (1970), Koler et
al. (1971), and Lie-Injo et al. (1971) provided electrophoretic
observations and genetic interpretations of hemoglobin H.

INHERITANCE

Necheles et al. (1966) provided evidence that Hb H disease results from
mating of a parent with alpha-thalassemia and a parent with a silent H
gene, and that double heterozygosity is necessary for Hb H disease. The
findings of Na-Nakorn et al. (1969) led to roughly the same conclusion.
Among the newborn offspring of persons with Hb H, they found some with 1
to 2% Hb Bart's and others with 5 to 6%. They suggested that these 2
types of children are heterozygous for 2 different alpha-thal genes, one
of which is not detectable in the adult heterozygote.

CLINICAL FEATURES

- Deletional Hemoglobin H Disease

Hb H disease is generally thought to be a mild disorder. However, there
is marked phenotypic variability ranging from asymptomatic, to needing
periodic transfusions, to severe anemia with hemolysis and
hepatosplenomegaly, to fatal hydrops fetalis in utero. Patients with
identical alpha-globin genotypes can have different phenotypes,
suggesting that there are other genetic and/or environmental factors
that can affect phenotypic expression of Hb H disease (summary by Chui
et al., 2003).

Lal et al. (2011) studied 60 patients with deletional Hb H disease
identified by newborn screening. Although originally assumed to be an
Asian-only phenotype, among these patients 15% had 1 or both parents
with African American ancestry. Growth was normal in patients with
deletional Hb H during the first decade. Height-for-age percentiles for
deletional Hb H patients were below the mean but above -1 Z score for
children through the age of 12 years. Most children with deletional Hb H
did not require blood transfusion; only 1 was required in a child under
age 20 years, a 2-year-old boy with severe pneumonia who required
mechanical ventilation. In patients over 20 years of age, 2 adults
required transfusion: one was a 26-year-old woman with hemoglobin level
of 7.6 g/dl who required transfusion during a febrile illness, and the
other was a 30-year-old female who was undergoing surgery. No patients
with deletional Hb H required splenectomy, and serum ferritin levels did
not increase significantly between birth and 18 years. Iron overload did
not generally manifest in patients with deletional Hb H prior to the
third decade.

- Nondeletional Hemoglobin H Disease

In contrast to beta-thalassemia, nondeletional alpha(+)-thalassemia
mutations are relatively uncommon. The alpha-2 globin gene (HBA2;
141850) accounts for 2 to 3 times more alpha-globin mRNA and
alpha-globin chain production than the alpha-1 gene. Therefore, point
mutations of the alpha-2-globin gene generally cause more severe anemia
than the same mutations involving the alpha-1-globin gene. Patients with
nondeletional Hb H disease usually are more anemic, more symptomatic,
more prone to have significant hepatosplenomegaly, and more likely to
require transfusions (summary by Chui et al., 2003).

The form of nondeletional hemoglobin H disease termed Hb H Constant
Spring arises from a deletion removing both alpha-globin genes on one
chromosome 16 and the alpha(+)-thalassemia mutation hemoglobin Constant
Spring (X142Q; 141850.0001) on the other chromosome 16. This
hemoglobinopathy is found predominantly in persons of Southeast Asian
ancestry. Lal et al. (2011) studied 23 patients with Hb H Constant
Spring. Patients with Hb H Constant Spring exhibited growth deficits
beginning in infancy. Anemia was more severe in patients with Hb H
Constant Spring at all ages, and acute worsening of anemia with
infections requiring urgent blood transfusions was observed in patients
with Hb H Constant Spring but not in those with deletional Hb H. The
probability of receiving at least 1 transfusion by the age of 20 years
was 3% for patients with deletional Hb H and 80% for those with Hb H
Constant Spring (p less than 0.001). Among patients with Hb H Constant
Spring, transfusions occurred in 13% of infants and 50% of children
under the age of 6 years; splenectomy was associated with a significant
improvement in hemoglobin levels (P = 0.01) and a reduction in the
number of transfusions. Patients with Hb H Constant Spring were of
Chinese, Laotian, and Cambodian ethnicity. Patients with Hb H Constant
Spring had a very high risk of severe anemia leading to urgent blood
transfusions. Transfusions were precipitated by infections in 37 events
(82%) with the majority of events (60%) diagnosed as viral illness owing
to an unknown source or organism. Five of 23 patients with Hb H Constant
Spring underwent splenectomy between the ages of 3.9 and 13.0 years
because of the need for frequent blood transfusion. The average baseline
hemoglobin level before splenectomy was 6.8 (range, 6.4 to 7.4), which
increased to 9.7 (range, 7.0 to 11.3) after splenectomy (P = 0.01).
Splenectomy reduced or eliminated acute hemolytic episodes requiring
urgent transfusion in 4 of the 5 patients. Hepatic iron was higher in
patients with Hb H Constant Spring, and these patients had an increased
number of annual clinic visits and increased number of annual hospital
admissions by a factor of 3.9 as compared with patients with deletional
hemoglobin H. Lal et al. (2011) stated that Hb H Constant Spring should
be recognized as a distinct thalassemia syndrome with a high risk of
life-threatening anemia during febrile illness.

Hill et al. (1987) described a unique nondeletion form of Hb H disease
in Papua New Guinea: all 4 alpha genes were intact.

POPULATION GENETICS

Hb H disease is found in many parts of the world, including Southeast
Asian, Middle Eastern, and Mediterranean populations. It is particularly
prevalent in Southeast Asia and in southern China, because of the high
carrier frequencies of the --(SEA) deletion and to a lesser extent the
--(FIL) deletion there. Of a Thailand population of 62 million people,
it was estimated that 7,000 infants with Hb H disease were born
annually, and that there were 420,000 patients with Hb H disease in that
country (summary by Chui et al., 2003).

Pressley et al. (1980) showed that the form of hemoglobin H that is
extraordinarily frequent in the population of the eastern Saudi Arabian
oasis is the result of a different aberration of the alpha-globin
haplotype than is Hb H in other populations.

Zeinali et al. (2011) remarked that while unpublished data from a study
of Hb H disease in Iran were consistent with the observations of Lal et
al. (2011) regarding deletional Hb H disease, those results showed more
diversity in the genotype and clinical presentation of nondeletional Hb
H disease. Zeinali et al. (2011) concluded that their data and those of
others consistent with it from the Mediterranean and the Middle East
will be useful for clinicians treating patients from those regions in
other countries. Vichinsky and Lal (2011) replied that in general the
data of Zeinali et al. (2011) provided support for their observations
that deletional Hb H disease is relatively benign and nondeletional Hb H
is moderately severe. However, many other genetic variables affect
phenotype, including involvement of the alpha-2 globin gene.
Environmental factors are a major determination of severity. In their
study, minor febrile illnesses triggered severe anemia in patients with
hemoglobin Constant Spring, and splenectomy reduced or eliminated these
hemolytic events.

The estimated number of worldwide annual births of patients with Hb H
disease is 9,568 and with Hb Bart's hydrops is 5,183 (Modell and
Darlison, 2008 and Weatherall, 2010).

MOLECULAR GENETICS

Hemoglobin H disease results from the inactivation of 3 of the 4
alpha-globin genes on both chromosomes 16. There are more than 20 known
natural deletions that remove both alpha-globin genes on the same
chromosome 16 (in cis) or the complete zeta-alpha-globin gene cluster,
and they are known as the alpha-0-thalassemia mutations. In addition,
there are rare deletions that silence alpha-globin gene expression by
removing the HS-regulatory sequences upstream of the zeta-alpha-globin
gene cluster (summary by Chui et al., 2003).

The southeast Asian deletion of alpha-0-thalassemia, termed --(SEA), is
approximately 19.3 kb and removes both alpha-globin genes in cis but
spares the embryonic zeta-globin gene. This mutation is the most common
cause for Hb H disease and hydrops fetalis syndrome in that part of the
world. In addition, the --(FIL), --(MED), and -(alpha20.5) deletions are
relatively common in the Philippines and in the Mediterranean region,
respectively (summary by Chui et al., 2003).

Chui et al. (2003) reviewed the genotypes of 319 patients with Hb H
disease from California, Hong Kong, and Ontario reported during the
foregoing 2 years. Of those patients, 266 (83%) had deletional Hb H
disease. The most common genotype was --(SEA)/-(alpha3.7), found in 175
patients (55%), followed by --(SEA)/-(alpha4.2) in 37 patients (12%),
and --(FIL)/-(alpha3.7) in 36 patients (11%). Fifty-three patients (17%)
had nondeletional Hb H disease. The most prevalent genotype among this
subgroup was --(SEA)/Constant Spring, found in 31 patients (10%). Among
the 638 chromosomes from these 319 patients, --(SEA) was found in 263
(41%), -(alpha3.7) in 224 (35%), -(alpha4.2) in 42 (7%), --(FIL) in 38
(6%), and Constant Spring in 32 chromosomes (5%). The 14 remaining
mutations were found in 39 chromosomes (6%). In the Mediterranean
region, the most common deletion removing both alpha-globin genes in cis
is the --(MED) deletion. Among 78 Cypriot patients with Hb H disease,
79% had the --(MED) deletion and 17% had the -(alpha20.5) deletion.

*FIELD* RF
1. Chui, D. H. K.; Fucharoen, S.; Chan, V.: Hemoglobin H disease:
not necessarily a benign disorder. Blood 101: 791-800, 2003.

2. Hill, A. V. S.; Thein, S. L.; Mavo, B.; Weatherall, D. J.; Clegg,
J. B.: Non-deletion haemoglobin H disease in Papua New Guinea. J.
Med. Genet. 24: 767-771, 1987.

3. Jones, R. T.; Schroeder, W. A.; Balog, J. E.; Vinograd, J. R.:
Gross structure of hemoglobin H. J. Am. Chem. Soc. 81: 3161 only,
1959.

4. Kattamis, C.; Lehmann, H.: The genetical interpretation of haemoglobin
H disease. Hum. Hered. 20: 156-164, 1970.

5. Koler, R. D.; Jones, R. T.; Wasi, P.; Pootrakul, S. N.: Genetics
of haemoglobin H and alpha-thalassaemia. Ann. Hum. Genet. 34: 371-377,
1971.

6. Lal, A.; Goldrich, M. L.; Haines, D. A.; Azimi, M.; Singer, S.
T.; Vichinsky, E. P.: Heterogeneity of hemoglobin H disease in childhood. New
Eng. J. Med. 364: 710-718, 2011.

7. Lie-Injo, L. E.; Lopez, C. G.; Lopes, M.: Inheritance of haemoglobin
H disease: a new aspect. Acta Haemat. 46: 106-120, 1971.

8. Modell, B.; Darlison, M.: Global epidemiology of haemoglobin disorders
and derived service indicators. Bull. World Health Organ. 86: 480-487,
2008.

9. Na-Nakorn, S.; Wasi, P.; Pornpatkul, M.; Pootrakul, S. N.: Further
evidence for a genetic basis of haemoglobin H disease from newborn
offspring of patients. Nature 223: 59-60, 1969.

10. Necheles, T. F.; Cates, M.; Sheehan, R. G.; Meyer, H. J.: Hemoglobin
H disease. A family study. Blood 28: 501-512, 1966.

11. Pressley, L.; Higgs, D. R.; Clegg, J. B.; Perrine, R. P.; Pembrey,
M. E.; Weatherall, D. J.: A new genetic basis for hemoglobin-H disease. New
Eng. J. Med. 303: 1383-1388, 1980.

12. Rigas, D. A.; Koler, R. D.; Osgood, E. E.: New hemoglobin possessing
a higher electrophoretic mobility than normal adult hemoglobin. Science 121:
372 only, 1955.

13. Vichinsky, E.; Lal, A,: Reply to Zeinali et al. (Letter) New
Eng. J. Med. 364: 2071 only, 2011.

14. Weatherall, D. J.: The inherited diseases of hemoglobin are an
emerging global health burden. Blood 115: 4331-4336, 2010.

15. Zeinali, S.; Fallah, M.-S.; Bagherian, H.: Comment on heterogeneity
of hemoglobin H disease in childhood. (Letter) New Eng. J. Med. 364:
2070-2071, 2011.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/14/2013
Anne M. Stumpf - updated: 11/4/2011

*FIELD* CD
Anne M. Stumpf: 5/16/2011

*FIELD* ED
alopez: 02/20/2013
ckniffin: 2/14/2013
alopez: 11/4/2011
terry: 8/1/2011
alopez: 7/27/2011
alopez: 7/25/2011

RBCC Red Blood Cell Collection

Full text data of HBA1