RBCC Red Blood Cell Collection

HBG2 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Hemoglobin subunit gamma-2 (Gamma-2-globin; Hb F Ggamma; Hemoglobin gamma-2 chain; Hemoglobin gamma-G chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00464992
IPI00464992 Hemoglobin gamma-G Gamma chains make up the fetal hemoglobin F, in combination with alpha chains 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 P69892
ID HBG2_HUMAN Reviewed; 147 AA.
AC P69892; A8MZE0; P02096; P62027; Q14491; Q68NH9; Q96FH6; Q96FH7;
read moreDT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 104.
DE RecName: Full=Hemoglobin subunit gamma-2;
DE AltName: Full=Gamma-2-globin;
DE AltName: Full=Hb F Ggamma;
DE AltName: Full=Hemoglobin gamma-2 chain;
DE AltName: Full=Hemoglobin gamma-G chain;
GN Name=HBG2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7438203; DOI=10.1016/0092-8674(80)90426-2;
RA Slightom J.L., Blechl A.E., Smithies O.;
RT "Human fetal G gamma- and A gamma-globin genes: complete nucleotide
RT sequences suggest that DNA can be exchanged between these duplicated
RT genes.";
RL Cell 21:627-638(1980).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7250702; DOI=10.1016/0378-1119(80)90103-1;
RA Cavallesco C., Forget B.G., Deriel J.K., Wilson L.B., Wilson J.T.,
RA Weissman S.M.;
RT "Nucleotide sequence of human G gamma globin messenger RNA.";
RL Gene 12:215-221(1980).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT M-CIRCLEVILLE LEU-64.
RA Kutlar F., Shell R.D., Elam D., Holley L., Nechtman J., Kutlar A.;
RT "A new G-gamma globin chain variant (His63Leu), hemoglobin M-
RT Circleville found in a Caucasian family.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Bone marrow, Lung, and Placenta;
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 [6]
RP PROTEIN SEQUENCE OF 2-147.
RX PubMed=14087393; DOI=10.1021/bi00905a016;
RA Schroeder W.A., Shelton J.R., Shelton J.B., Cormick J., Jones R.T.;
RT "The amino acid sequence of the gamma chain of human fetal
RT hemoglobin.";
RL Biochemistry 2:992-1008(1963).
RN [7]
RP PROTEIN SEQUENCE OF 2-60; 67-77 AND 84-147, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 122-147.
RX PubMed=2581851; DOI=10.1016/0378-1119(85)90093-9;
RA Lang K.M., Spritz R.A.;
RT "Cloning specific complete polyadenylylated 3'-terminal cDNA
RT segments.";
RL Gene 33:191-196(1985).
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF HETERODIMER WITH ALPHA CHAIN.
RX PubMed=881729; DOI=10.1016/S0022-2836(77)80158-7;
RA Frier J.A., Perutz M.F.;
RT "Structure of human foetal deoxyhaemoglobin.";
RL J. Mol. Biol. 112:97-112(1977).
RN [11]
RP ACETYLATION AT GLY-2.
RX PubMed=5554303;
RA Stegink L.D., Meyer P.D., Brummel M.C.;
RT "Human fetal hemoglobin F 1. Acetylation status.";
RL J. Biol. Chem. 246:3001-3007(1971).
RN [12]
RP VARIANT MALTA-1 ARG-118.
RX PubMed=5792729; DOI=10.1038/223311a0;
RA Cauchi M.N., Clegg J.B., Weatherall D.J.;
RT "Haemoglobin F(Malta): a new foetal haemoglobin variant with a high
RT incidence in Maltese infants.";
RL Nature 223:311-313(1969).
RN [13]
RP VARIANT AUCKLAND ASN-8.
RX PubMed=4429671;
RA Carrell R.W., Owen M.C., Anderson R., Berry E.;
RT "Haemoglobin F Auckland G gamma 7 Asp leads to Asn: further evidence
RT for multiple genes for the gamma chain.";
RL Biochim. Biophys. Acta 365:323-327(1974).
RN [14]
RP VARIANT PORT-ROYAL ALA-126.
RX PubMed=4846278; DOI=10.1111/j.1365-2141.1974.tb06798.x;
RA Brimhall B., Vedvick T.S., Jones R.T., Ahern E., Palomino E.,
RA Ahern V.;
RT "Haemoglobin F Port Royal (alpha2G gamma2 125 Glu leads to Ala).";
RL Br. J. Haematol. 27:313-318(1974).
RN [15]
RP VARIANT MALAYSIA CYS-2.
RX PubMed=4837284;
RA Lie-Injo L.E., Kamuzora H., Lehmann H.;
RT "Haemoglobin F Malaysia: alpha 2, gamma 2 1(NA1) glycine-->cysteine;
RT 136 glycine.";
RL J. Med. Genet. 11:25-30(1974).
RN [16]
RP VARIANT POOLE GLY-131.
RX PubMed=1127124;
RA Lee-Potter J.P., Deacon-Smith R.A., Simpkiss M.J., Kamuzora H.,
RA Lehmann H.;
RT "A new cause of haemolytic anaemia in the newborn. A description of an
RT unstable fetal haemoglobin: F Poole, alpha2-G-gamma2 130 tryptophan
RT yields glycine.";
RL J. Clin. Pathol. 28:317-320(1975).
RN [17]
RP VARIANTS MELBOURNE ARG-17 AND CARLTON LYS-122.
RX PubMed=836882; DOI=10.1016/0005-2795(77)90020-4;
RA Brennan S.O., Smith M.B., Carrell R.W.;
RT "Haemoglobin F Melbourne Ggamma 16 Gly leads to Arg and haemoglobin F
RT carlton Ggamma 121 Glu leads to Lys. Further evidence for varied
RT activity of gamma-chain genes.";
RL Biochim. Biophys. Acta 490:452-455(1977).
RN [18]
RP VARIANT MEINOHAMA GLY-6.
RX PubMed=6172403;
RA Ohta Y., Saito S., Fujita S., Wilson J.B., Lam H., Huisman T.H.J.;
RT "Hb F-Meinohama or alpha 2 gamma 2 (5 Glu replaced by Gly; 75 Ile; 136
RT Gly).";
RL Hemoglobin 5:565-570(1981).
RN [19]
RP VARIANT LODZ ARG-45.
RX PubMed=6814491; DOI=10.1016/0167-4838(82)90353-3;
RA Honig G.R., Koshy M., Schroeder W.A., Shelton J.B., Shelton J.R.;
RT "Hemoglobin F Lodz (G gamma I 44 Ser replaced by Arg). A newly
RT identified variant from an American infant of Polish descent.";
RL Biochim. Biophys. Acta 707:213-216(1982).
RN [20]
RP VARIANT KINGSTON ARG-56.
RX PubMed=6186522; DOI=10.1016/0014-5793(82)81307-0;
RA Serjeant G.R., Serjeant B.E., Lehmann H., Dukes M., Robb L.;
RT "Hb F Kingston (G gamma 55 [D6] Met leads to Arg).";
RL FEBS Lett. 150:77-80(1982).
RN [21]
RP VARIANT CALTECH GLN-121.
RX PubMed=6186635;
RA Shelton J.B., Shelton J.R., Espinueva Z., Huynh V., Schroeder W.A.,
RA Powars D.;
RT "Hemoglobin F-Caltech: alpha 2 G gamma 2 120Lys replaced by Gln.";
RL Hemoglobin 6:577-592(1982).
RN [22]
RP VARIANT COLUMBUS-GA ASN-95.
RX PubMed=6186636;
RA Nakatsuji T., Lam H., Wilson J.B., Webber B.B., Huisman T.H.J.;
RT "Hb F-Columbus-Ga or alpha 2 G gamma 2 94(FGl) Asp replaced by Asn.";
RL Hemoglobin 6:593-598(1982).
RN [23]
RP VARIANT KENNESTONE ARG-78.
RX PubMed=6192110;
RA Nakatsuji T., Lam H., Huisman T.H.J.;
RT "Hb F-Kennestone or alpha 2G gamma 2 (EF1)77 His leads to Arg observed
RT in a Caucasian baby.";
RL Hemoglobin 7:267-270(1983).
RN [24]
RP VARIANT LA GRANGE LYS-102.
RX PubMed=6206897; DOI=10.1016/0167-4838(84)90208-5;
RA Nakatsuji T., Shimizu K., Huisman T.H.J.;
RT "Hb F-La Grange or alpha 2 gamma 2 101(G3)Glu-->Lys; 75Ile; 136Gly: a
RT high oxygen affinity fetal hemoglobin variant observed in a Caucasian
RT newborn.";
RL Biochim. Biophys. Acta 789:224-228(1984).
RN [25]
RP VARIANT SHANGHAI ARG-67.
RX PubMed=2579547; DOI=10.1002/ajh.2830180303;
RA Zeng Y.T., Huang S.Z., Nakatsuji T., Huisman T.H.J.;
RT "-G gamma A gamma-thalassemia and gamma-chain variants in Chinese
RT newborn babies.";
RL Am. J. Hematol. 18:235-242(1985).
RN [26]
RP VARIANT TOKYO ILE-35.
RX PubMed=2581919;
RA Chen S.S., Wilson J.B., Webber B.B., Huisman T.H.J., Miwa S.,
RA Amenomori Y.;
RT "Hb F-Tokyo or alpha 2G gamma 2 34(B16)Val-->Ile, a silent gamma chain
RT variant detected by reverse phase high performance liquid
RT chromatography.";
RL Hemoglobin 9:25-32(1985).
RN [27]
RP VARIANT URUMQI GLY-23.
RX PubMed=2420748;
RA Hu H.Y., Ma M.S.;
RT "Hb F-Urumqi G gamma I22(B4)Asp-->Gly: a new fetal hemoglobin variant
RT found in a Uygur baby.";
RL Hemoglobin 10:15-20(1986).
RN [28]
RP VARIANTS ALBAICIN GLU-9 AND GLN-9.
RX PubMed=2435680;
RA de Pablos J.M., Wilson J.B., Kutlar A., Chen S.S., Huisman T.H.J.;
RT "Hb F-Albaicin or G gamma 8(A5)Lys-->Glu or Gln.";
RL Hemoglobin 10:655-659(1986).
RN [29]
RP VARIANTS FUCHU GLN-22 AND MINOO ARG-73.
RX PubMed=3120456;
RA Hayashi A., Wada Y., Matsuo T., Katakuse I., Matsuda H.;
RT "Neonatal screening and mass-spectrometric analysis of hemoglobin
RT variants in Japan.";
RL Acta Haematol. 78:114-118(1987).
RN [30]
RP VARIANT OAKLAND LYS-27.
RX PubMed=2442122;
RA Kleman K., Lubin B., Wilson J.B., Kutlar A., Webber B.B.,
RA Huisman T.H.J.;
RT "Hb F-Oakland or alpha 2G gamma I2(26)(B8)Glu-->Lys.";
RL Hemoglobin 11:181-183(1987).
RN [31]
RP VARIANT CLARKE ASN-66.
RX PubMed=2442123;
RA Kutlar A., Kutlar F., Wilson J.B., Webber B.B., Gonzalez Redondo J.M.,
RA Huisman T.H.J.;
RT "Hb F-Clarke or alpha 2G gamma 2(65)(E9)Lys-->Asn.";
RL Hemoglobin 11:185-188(1987).
RN [32]
RP VARIANT GRANADA VAL-23.
RX PubMed=2459082;
RA de Pablos J.M., Clegg J.B.;
RT "Hb F-Granada or alpha 2G gamma (2)22(B4)Asp-->Val: a new human fetal
RT hemoglobin variant.";
RL Hemoglobin 12:405-407(1988).
RN [33]
RP VARIANT AUSTELL LYS-41.
RX PubMed=2459083;
RA Kutlar A., Kutlar F., Wilson J.B., Webber B.B., Hu H., Huisman T.H.J.;
RT "Hb F-Austell or alpha 2G gamma (2)40(C6)Arg-->Lys.";
RL Hemoglobin 12:409-411(1988).
RN [34]
RP VARIANT TNCY TYR-64.
RX PubMed=2483933;
RA Glader B.E., Zwerdling D., Kutlar F., Kutlar A., Wilson J.B.,
RA Huisman T.H.J.;
RT "Hb F-M-Osaka or alpha 2G gamma 2(63)(E7)His-->Tyr in a Caucasian male
RT infant.";
RL Hemoglobin 13:769-773(1989).
RN [35]
RP VARIANT TNCY TYR-93.
RX PubMed=2470017;
RA Priest J.R., Watterson J., Jones R.T., Faassen A.E., Hedlund B.E.;
RT "Mutant fetal hemoglobin causing cyanosis in a newborn.";
RL Pediatrics 83:734-736(1989).
RN [36]
RP VARIANT BROOKLYN GLN-67.
RX PubMed=1703138;
RA Plaseska D., Li H.-J., Wilson J.B., Kutlar F., Kutlar A.,
RA Huisman T.H.J., Kulpa J.;
RT "Hb F-Brooklyn or alpha 2G gamma 2(66)(E10)Lys-->Gln.";
RL Hemoglobin 14:213-216(1990).
RN [37]
RP VARIANT ONODA TYR-147.
RX PubMed=1703139;
RA Harano T., Harano K., Doi K., Ueda S., Imai K., Ohba Y., Kutlar F.,
RA Huisman T.H.J.;
RT "Hb F-Onoda or alpha 2G gamma 2(146)(HC3)His-->Tyr, a newly discovered
RT fetal hemoglobin variant in a Japanese newborn.";
RL Hemoglobin 14:217-222(1990).
RN [38]
RP VARIANT CATALONIA ARG-16.
RX PubMed=1706691;
RA Plaseska D., Wilson J.B., Kutlar F., Font L., Baiget M.,
RA Huisman T.H.J.;
RT "Hb F-Catalonia or alpha 2G gamma(2)15(A12)Trp-->Arg.";
RL Hemoglobin 14:511-516(1990).
RN [39]
RP VARIANT CHARLOTTE THR-76.
RX PubMed=1714434;
RA Plaseska D., Kutlar F., Wilson J.B., Fei Y.J., Huisman T.H.J.;
RT "Hb F-Charlotte, an A gamma variant with a threonine residue in
RT position gamma 75 and a glycine residue in position gamma 136.";
RL Hemoglobin 14:617-625(1990).
RN [40]
RP VARIANT COSENZA GLU-26.
RX PubMed=1726095;
RA Qualtieri A., Crescibene L., Bagala A., de Marco E.V., Bria M.,
RA Brancati C.;
RT "Hb F-Cosenza or G gamma 25(B7)Gly-->Glu: a new fast-moving fetal
RT hemoglobin variant.";
RL Hemoglobin 15:509-515(1991).
RN [41]
RP VARIANT SASKATOON LYS-22.
RX PubMed=8144355;
RA Pobedimskaya D.D., Molchanova T.P., Huisman T.H.J., Harding S.R.,
RA Bakanec R.;
RT "Hb F-Saskatoon or alpha 2G gamma (2)21(B3)Glu-->Lys observed in a
RT North American indian newborn.";
RL Hemoglobin 17:547-549(1993).
RN [42]
RP VARIANT MACEDONIA-II ASN-105.
RX PubMed=7713741;
RA Plaseska D., Panovska-Popovska S., Lazarevski M., Efremov G.D.;
RT "Hb F-Macedonia-II [G gamma 104(G6)Lys-->Asn]: a new gamma chain
RT variant.";
RL Hemoglobin 18:373-382(1994).
RN [43]
RP VARIANT TNCY SER-42.
RX PubMed=7741137; DOI=10.1002/ajh.2830490108;
RA Kohli-Kumar M., Zwerdling T., Rucknagel D.L.;
RT "Hemoglobin F-Cincinnati, alpha 2G gamma 2 41(C7) Phe-->Ser in a
RT newborn with cyanosis.";
RL Am. J. Hematol. 49:43-47(1995).
RN [44]
RP VARIANTS EMIRATES GLU-60 AND SACROMONTE GLN-60.
RX PubMed=7558873;
RA Abbes S., Fitzgerald P.A., Varady E., Girot R., Pic P., Blouquit Y.,
RA Ducrocq R., Drupt F., Wajcman H.;
RT "Two fetal hemoglobin variants affecting the same residue: Hb F-
RT Emirates [G gamma 59(E3)Lys-->Glu] and Hb F-Sacromonte [G gamma
RT 59(E3)Lys-->Gln].";
RL Hemoglobin 19:173-182(1995).
RN [45]
RP VARIANT VELETA GLY-23.
RX PubMed=8718700;
RA de Pablos Gallego J.M., Gu L.H., Leonova J.Y., Huisman T.H.J.;
RT "Hb F-Veleta or alpha 2 G gamma(2)40(C6)Arg-->Gly.";
RL Hemoglobin 19:407-411(1995).
RN [46]
RP VARIANT WAYNESBORO THR-76.
RX PubMed=8718701;
RA Gu L.H., Oner C., Huisman T.H.J.;
RT "The G gamma T chain (G gamma 75 Thr; 136 Gly) in Hb F-Charlotte is
RT the product of an A gamma gene with a limited gene conversion and that
RT in Hb F-Waynesboro of a mutated G gamma gene.";
RL Hemoglobin 19:413-418(1995).
RN [47]
RP VARIANT LESVOS THR-76.
RX PubMed=8566966; DOI=10.1007/BF02265278;
RA Papadakis M.N., Patrinos G.P., Drakoulakou O., Loutradi-Anagnostou A.;
RT "HbF-Lesvos: an HbF variant due to a novel G gamma mutation (G gamma
RT 75 ATA-->ACA) detected in a Greek family.";
RL Hum. Genet. 97:260-262(1996).
RN [48]
RP VARIANT CALABRIA LEU-119.
RX PubMed=10722114;
RA Manca L., Cherchi L., De Rosa M.C., Giardina B., Masala B.;
RT "A new, electrophoretically silent, fetal hemoglobin variant: Hb F-
RT Calabria Ggamma118(GH1)Phe-->Leu.";
RL Hemoglobin 24:37-44(2000).
RN [49]
RP VARIANTS CLAMART ASN-18 AND OULED RABAH LYS-20.
RX PubMed=10722115;
RA Wajcman H., Borensztajn K., Riou J., Prome D., Hurtrel D.,
RA Bardakdjian J., Lena-Russo D., Amouroux I., Ducrocq R.;
RT "Two new Ggamma chain variants: Hb F-Clamart [gamma17(A14)Lys-->Asn]
RT and Hb F-Ouled Rabah [gamma19(B1)Asn-->Lys].";
RL Hemoglobin 24:45-52(2000).
RN [50]
RP VARIANT COIGNERES VAL-76.
RX PubMed=11791877; DOI=10.1081/HEM-100107881;
RA Wajcman H., Yapo A.P., Riou J., Prome D., Richelme-David S.,
RA Hurtrel D., Bardakdjian-Michau J.;
RT "A new Ggamma chain variant: Hb F-Coignieres
RT [gamma75(E19)Ile-->Val].";
RL Hemoglobin 25:425-428(2001).
RN [51]
RP VARIANT BONHEIDEN PRO-39.
RX PubMed=15645283; DOI=10.1007/s00431-004-1614-7;
RA Van den Driessche M., Moerman J., Moens M., Van Eldere S.,
RA Derclaye I., Philippe M.;
RT "Severe hereditary haemolytic anaemia in a Caucasian newborn: a new
RT fetal haemoglobin variant Hb F-Bonheiden ((G)gamma 38(C4)
RT Thr-->Pro).";
RL Eur. J. Pediatr. 164:261-262(2005).
RN [52]
RP VARIANT BRON ALA-21.
RX PubMed=16370494; DOI=10.1080/03630260500312725;
RA Lacan P., Burnichon N., Becchi M., Zanella-Cleon I., Aubry M.,
RA Couprie N., Francina A.;
RT "A new G(gamma) chain variant: Hb F-Bron [gamma20(B2)Val-->Ala].";
RL Hemoglobin 29:301-305(2005).
RN [53]
RP VARIANT TNCY LEU-64, AND CHARACTERIZATION OF VARIANT TNCY TYR-64.
RX PubMed=19065339; DOI=10.1080/03630260802507915;
RA Dainer E., Shell R., Miller R., Atkin J.F., Pastore M., Kutlar A.,
RA Zhuang L., Holley L., Davis D.H., Kutlar F.;
RT "Neonatal cyanosis due to a novel fetal hemoglobin: Hb F-Circleville
RT [Ggamma63(E7)His-->Leu, CAT>CTT].";
RL Hemoglobin 32:596-600(2008).
RN [54]
RP VARIANT TNCY MET-68, AND CHARACTERIZATION OF VARIANT TNCY MET-68.
RX PubMed=21561349; DOI=10.1056/NEJMoa1013579;
RA Crowley M.A., Mollan T.L., Abdulmalik O.Y., Butler A.D., Goodwin E.F.,
RA Sarkar A., Stolle C.A., Gow A.J., Olson J.S., Weiss M.J.;
RT "A hemoglobin variant associated with neonatal cyanosis and anemia.";
RL N. Engl. J. Med. 364:1837-1843(2011).
CC -!- FUNCTION: Gamma chains make up the fetal hemoglobin F, in
CC combination with alpha chains.
CC -!- SUBUNIT: Heterotetramer of two alpha chains and two gamma chains
CC in fetal hemoglobin (Hb F).
CC -!- TISSUE SPECIFICITY: Red blood cells.
CC -!- DEVELOPMENTAL STAGE: Expressed until four or five weeks after
CC birth.
CC -!- PTM: Acetylation of Gly-2 converts Hb F to the minor Hb F1.
CC -!- DISEASE: Cyanosis transient neonatal (TNCY) [MIM:613977]: A
CC disorder characterized by cyanosis in the fetus and neonate, due
CC to a defect in the fetal hemoglobin chain which has reduced
CC affinity for oxygen. Some patients develop anemia resulting from
CC increased destruction of red cells containing abnormal or unstable
CC hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months
CC of age or earlier, as the adult beta-globin chain is produced and
CC replaces the fetal gamma-globin chain. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the globin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB50159.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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;=HBG2";
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CC -----------------------------------------------------------------------
DR EMBL; M91036; AAB59428.1; -; Genomic_DNA.
DR EMBL; M91037; AAA58492.1; -; Genomic_DNA.
DR EMBL; U01317; AAA16331.1; -; Genomic_DNA.
DR EMBL; V00515; CAA23773.1; -; Genomic_DNA.
DR EMBL; M15386; AAB50159.1; ALT_INIT; mRNA.
DR EMBL; AY662983; AAT98611.1; -; Genomic_DNA.
DR EMBL; AK290492; BAF83181.1; -; mRNA.
DR EMBL; BC010914; AAH10914.1; -; mRNA.
DR EMBL; BC029387; AAH29387.1; -; mRNA.
DR EMBL; BC130457; AAI30458.1; -; mRNA.
DR EMBL; BC130459; AAI30460.1; -; mRNA.
DR EMBL; M11427; AAA35957.1; -; mRNA.
DR PIR; A90803; HGHUA.
DR RefSeq; NP_000175.1; NM_000184.2.
DR UniGene; Hs.302145; -.
DR UniGene; Hs.702189; -.
DR PDB; 1FDH; X-ray; 2.50 A; G/H=2-147.
DR PDB; 4MQJ; X-ray; 1.80 A; B/D/F/H=3-147.
DR PDB; 4MQK; X-ray; 2.24 A; B/D/F/H=2-147.
DR PDBsum; 1FDH; -.
DR PDBsum; 4MQJ; -.
DR PDBsum; 4MQK; -.
DR ProteinModelPortal; P69892; -.
DR SMR; P69892; 2-147.
DR IntAct; P69892; 3.
DR MINT; MINT-1200269; -.
DR STRING; 9606.ENSP00000338082; -.
DR PhosphoSite; P69892; -.
DR DMDM; 56749861; -.
DR PaxDb; P69892; -.
DR PRIDE; P69892; -.
DR Ensembl; ENST00000336906; ENSP00000338082; ENSG00000196565.
DR Ensembl; ENST00000380259; ENSP00000369609; ENSG00000196565.
DR GeneID; 3048; -.
DR KEGG; hsa:3048; -.
DR UCSC; uc001maj.1; human.
DR CTD; 3048; -.
DR GeneCards; GC11M005274; -.
DR HGNC; HGNC:4832; HBG2.
DR HPA; CAB016143; -.
DR MIM; 142250; gene.
DR MIM; 613977; phenotype.
DR neXtProt; NX_P69892; -.
DR Orphanet; 280615; Hemoglobinopathy Toms River.
DR Orphanet; 46532; Hereditary persistence of fetal hemoglobin - beta-thalassemia.
DR Orphanet; 251380; Hereditary persistence of fetal hemoglobin - sickle cell disease.
DR PharmGKB; PA29207; -.
DR eggNOG; NOG331950; -.
DR HOVERGEN; HBG009709; -.
DR KO; K13824; -.
DR PhylomeDB; P69892; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; HBG2; human.
DR EvolutionaryTrace; P69892; -.
DR GeneWiki; HBG2; -.
DR GenomeRNAi; 3048; -.
DR NextBio; 12067; -.
DR PRO; PR:P69892; -.
DR ArrayExpress; P69892; -.
DR Bgee; P69892; -.
DR CleanEx; HS_HBG2; -.
DR Genevestigator; P69892; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005833; C:hemoglobin complex; IEA:InterPro.
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:0007596; P:blood coagulation; TAS:Reactome.
DR Gene3D; 1.10.490.10; -; 1.
DR InterPro; IPR000971; Globin.
DR InterPro; IPR009050; Globin-like.
DR InterPro; IPR012292; Globin_dom.
DR InterPro; IPR002337; Haemoglobin_b.
DR PANTHER; PTHR11442:SF7; PTHR11442:SF7; 1.
DR Pfam; PF00042; Globin; 1.
DR PRINTS; PR00814; BETAHAEM.
DR SUPFAM; SSF46458; SSF46458; 1.
DR PROSITE; PS01033; GLOBIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Heme; Iron;
KW Metal-binding; Oxygen transport; Polymorphism; Reference proteome;
KW Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 147 Hemoglobin subunit gamma-2.
FT /FTId=PRO_0000053254.
FT METAL 64 64 Iron (heme distal ligand).
FT METAL 93 93 Iron (heme proximal ligand).
FT MOD_RES 2 2 N-acetylglycine; in form Hb F1.
FT VARIANT 2 2 G -> C (in Malaysia).
FT /FTId=VAR_003123.
FT VARIANT 6 6 E -> G (in Meinohama).
FT /FTId=VAR_003126.
FT VARIANT 8 8 D -> N (in Auckland).
FT /FTId=VAR_003129.
FT VARIANT 9 9 K -> E (in Albaicin).
FT /FTId=VAR_020643.
FT VARIANT 9 9 K -> Q (in Albaicin).
FT /FTId=VAR_020644.
FT VARIANT 13 13 T -> R (in Heather).
FT /FTId=VAR_020645.
FT VARIANT 16 16 W -> R (in Catalonia).
FT /FTId=VAR_003131.
FT VARIANT 17 17 G -> R (in Melbourne).
FT /FTId=VAR_003132.
FT VARIANT 18 18 K -> N (in Clamart).
FT /FTId=VAR_020646.
FT VARIANT 20 20 N -> K (in Ouled Rabah).
FT /FTId=VAR_020647.
FT VARIANT 21 21 V -> A (in Bron).
FT /FTId=VAR_030496.
FT VARIANT 22 22 E -> K (in Saskatoon).
FT /FTId=VAR_003133.
FT VARIANT 22 22 E -> Q (in Fuchu).
FT /FTId=VAR_003134.
FT VARIANT 23 23 D -> G (in Urumqi).
FT /FTId=VAR_020648.
FT VARIANT 23 23 D -> V (in Granada).
FT /FTId=VAR_003136.
FT VARIANT 26 26 G -> E (in Cosenza).
FT /FTId=VAR_003137.
FT VARIANT 27 27 E -> K (in Oakland).
FT /FTId=VAR_003139.
FT VARIANT 35 35 V -> I (in Tokyo).
FT /FTId=VAR_003140.
FT VARIANT 39 39 T -> P (in Bonheiden; causes severe
FT hereditary hemolytic anemia).
FT /FTId=VAR_030497.
FT VARIANT 41 41 R -> G (in Veleta).
FT /FTId=VAR_003144.
FT VARIANT 41 41 R -> K (in Austell).
FT /FTId=VAR_020649.
FT VARIANT 42 42 F -> S (in TNCY; hemoglobin Cincinnati).
FT /FTId=VAR_003146.
FT VARIANT 45 45 S -> R (in Lodz).
FT /FTId=VAR_003148.
FT VARIANT 56 56 M -> R (in Kingston).
FT /FTId=VAR_003150.
FT VARIANT 60 60 K -> E (in Emirates).
FT /FTId=VAR_003151.
FT VARIANT 60 60 K -> Q (in Sacromonte).
FT /FTId=VAR_003152.
FT VARIANT 64 64 H -> L (in TNCY; hemoglobin M-
FT Circleville).
FT /FTId=VAR_025336.
FT VARIANT 64 64 H -> Y (in TNCY; hemoglobin Osaka; the
FT presence of a tyrosine causes the
FT formation of a covalent link with heme
FT iron, so that the iron is stabilized in
FT the ferric form; when this occurs
FT methemoglobin is formed, oxygen can no
FT longer bind to heme and cyanosis occurs).
FT /FTId=VAR_003154.
FT VARIANT 66 66 K -> N (in Clarke).
FT /FTId=VAR_003155.
FT VARIANT 67 67 K -> Q (in Brooklyn).
FT /FTId=VAR_003157.
FT VARIANT 67 67 K -> R (in Shanghai).
FT /FTId=VAR_003156.
FT VARIANT 68 68 V -> M (in TNCY; hemoglobin Toms River;
FT the side chain of methionine decreases
FT both the affinity of oxygen for binding
FT to the mutant hemoglobin subunit via
FT steric hindrance and the rate at which it
FT does so; the mutant methionine is
FT converted to aspartic acid post-
FT translationally).
FT /FTId=VAR_065950.
FT VARIANT 73 73 G -> R (in Minoo).
FT /FTId=VAR_020650.
FT VARIANT 76 76 I -> T (in LesVos/Waynesboro/Charlotte;
FT dbSNP:rs1061234).
FT /FTId=VAR_020651.
FT VARIANT 76 76 I -> V (in Coigneres).
FT /FTId=VAR_030498.
FT VARIANT 78 78 H -> R (in Kennestone).
FT /FTId=VAR_003162.
FT VARIANT 81 81 D -> N (in Marietta).
FT /FTId=VAR_020652.
FT VARIANT 93 93 H -> Y (in TNCY; hemoglobin Fort Ripley;
FT dbSNP:rs35103459).
FT /FTId=VAR_003166.
FT VARIANT 95 95 D -> N (in Columbus-Ga).
FT /FTId=VAR_003167.
FT VARIANT 102 102 E -> K (in La Grange).
FT /FTId=VAR_003169.
FT VARIANT 105 105 K -> N (in Macedonia-II).
FT /FTId=VAR_003170.
FT VARIANT 118 118 H -> R (in Malta-1).
FT /FTId=VAR_003171.
FT VARIANT 119 119 F -> L (in Calabria).
FT /FTId=VAR_015740.
FT VARIANT 121 121 K -> Q (in Caltech; dbSNP:rs34703519).
FT /FTId=VAR_003172.
FT VARIANT 122 122 E -> K (in Carlton).
FT /FTId=VAR_020653.
FT VARIANT 126 126 E -> A (in Port-Royal).
FT /FTId=VAR_003174.
FT VARIANT 131 131 W -> G (in Poole; unstable).
FT /FTId=VAR_003176.
FT VARIANT 147 147 H -> Y (in Onoda; O(2) affinity up;
FT dbSNP:rs34807671).
FT /FTId=VAR_003179.
FT HELIX 6 18
FT HELIX 21 35
FT HELIX 37 42
FT HELIX 44 46
FT HELIX 52 56
FT HELIX 59 76
FT HELIX 77 81
FT HELIX 82 85
FT HELIX 87 95
FT HELIX 102 119
FT HELIX 120 122
FT HELIX 125 142
FT HELIX 143 146
SQ SEQUENCE 147 AA; 16126 MW; 8FCDC4441B416DDE CRC64;
MGHFTEEDKA TITSLWGKVN VEDAGGETLG RLLVVYPWTQ RFFDSFGNLS SASAIMGNPK
VKAHGKKVLT SLGDAIKHLD DLKGTFAQLS ELHCDKLHVD PENFKLLGNV LVTVLAIHFG
KEFTPEVQAS WQKMVTGVAS ALSSRYH
//

MIM 142250
*RECORD*
*FIELD* NO
142250
*FIELD* TI
*142250 HEMOGLOBIN, GAMMA G; HBG2
;;HEMOGLOBIN--GAMMA LOCUS, 136 GLYCINE
*FIELD* TX
read more
DESCRIPTION

The HBG2 and HBG1 (142200) genes encode the gamma chain of hemoglobin,
which combines with 2 alpha chains (HBA1; 141800) (alpha-2/gamma-2) to
form fetal hemoglobin. The 2 chains differ by a single amino acid at
codon 136: HBG1 contains an alanine at codon 136, whereas HBG2 contains
a glycine at codon 136 (Schroeder et al., 1968).

CLONING

Fritsch et al. (1980) isolated clones corresponding to the HBG1 and HBG2
genes as part of the beta-like globin gene cluster (HBB; 141900).

GENE STRUCTURE

Chen et al. (2008) identified a silencing element in the HBG2 promoter
between nucleotides -675 and -526. There is a GATA motif from
nucleotides -569 to -544 that binds the GATA1 (305371) transcription
factor and results in silencing of the gene in adults. This motif is
uniquely conserved in simian primates, who also have a fetal pattern of
gamma-globin gene expression.

GENE FUNCTION

Schroeder et al. (1968) provided evidence for the existence of 2 types
of gamma polypeptide chains, determined presumably by separate cistrons.
Although not distinguishable by most of the physical methods used,
sequencing has shown at least 1 amino acid difference: at position 136,
one type has glycine (G-gamma; HBG2) and the second type has alanine
(A-gamma; HBG1; 142200). Presumably the 2 loci arose by gene
duplication. Each mutation occurs, apparently, in only 1 of the gamma
cistrons; e.g., the mutation of Hb F(Malta) is in the glycine 136
cistron.

Huisman et al. (1972) concluded that there are usually 4 gamma
structural loci, 2 on each autosome. In the heterozygote, gamma-G chain
variants contribute either about one-fourth or one-eighth and the
gamma-A chain variants either about one-eighth or one-sixteenth of the
total HbF. The 4 postulated gamma loci, 2 gamma-G loci termed M and L by
these workers, and 2 gamma-A loci likewise termed M and L, produce gamma
chains in an approximate ratio of 4:2:2:1.

By a direct method involving hybridization of complementary DNA to total
human DNA, Old et al. (1976) demonstrated that man has 2 gamma-globin
genes per haploid genome. The ratio of G-gamma to A-gamma is fairly
constant (about 7:3) during the fetal period. The ratio declines
progressively during the postnatal gamma-to-beta switch, leading to an
average value of 2:3 in the small residual amount of HbF detectable in
normal adult blood. This switch in gamma ratio seems to occur by the
same mechanism as the gamma-beta switch (Comi et al., 1980).

For a discussion of the regulatory region of hemoglobin gamma, see
142200.

Foley et al. (2002) demonstrated that synthesis of STAT3-beta (102582)
by erythroleukemia and primary erythroid progenitor cells treated with
IL6 (147620) silences gamma-globin expression. They identified the
STAT3-like binding sequence in the promoter region of both the A-gamma
and G-gamma hemoglobins.

MOLECULAR GENETICS

Persons with 3 gamma-chain genes have been found (Trent et al., 1981);
this is not accompanied by hematologic abnormalities (Thein et al.,
1984). In the family studied by Thein et al. (1984), restriction enzyme
analysis indicated that the 3 gamma genes were 2 G-gamma and an A-gamma,
arranged 5-prime to 3-prime, respectively.

In the course of a survey of infants with gene-specific probes, Fei et
al. (1988) found a black infant with 5 gamma-globin genes. They
concluded that the 3 genes located between the 5-prime G-gamma and the
3-prime A-gamma genes were G-gamma genes with a possible 5-prime segment
derived from A-gamma. The high G-gamma level in the baby's HbF was
consistent with this view. The family could not be investigated to
determine the origin of the quintuplication of the gamma-globin gene.

Carver and Kutlar (1995) listed 37 gamma-chain variants in which the
mutation was in the HBG2 gene (as of January, 1995).

- Hereditary Persistence of Fetal Hemoglobin

The form of hereditary persistence of fetal hemoglobin (HPFH; 141749)
due to a point mutation in the promoter region 5-prime to the G-gamma
gene is referred to as the nondeletional type of HPFH. A number of
mutations have been identified that interfere with the normal process of
hemoglobin switching and result in hereditary persistence of fetal
hemoglobin. Several single-base substitutions located within the
promoter regions of the gamma genes appear to be responsible for the
HPFH phenotype. Metherall et al. (1988) demonstrated that the
beta-globin genes linked to 2 such mutations are normal. Their analysis,
which involved transient expression in HeLa cells, demonstrated that the
genes produce normal levels of correctly initiated, spliced, and
polyadenylated mRNA. Sequence analysis of the DNA for both of these
genes likewise demonstrated normal alleles. According to the authors,
these results support the hypothesis that the single basepair changes in
the promoter regions of the gamma genes are responsible for the decrease
in beta-globin expression and the increase in gamma gene expression in
patients with both of these forms of HPFH.

Collins et al. (1984, 1984, 1985) identified a C-to-G change at
nucleotide -202 in the promoter region of the HBG2 gene (142250.0026) as
a cause of hereditary persistence of fetal hemoglobin in the black
population.

In an Algerian family with HPFH, Zertal-Zidani et al. (1999) identified
a novel C-to-A transversion at position -114 in the distal CCAAT box of
the G-gamma globin gene promoter (142250.0046). This substitution
cosegregated with a unique beta-globin gene cluster haplotype.
Individuals heterozygous for this mutation exhibited moderate rise in
HbF levels (0.6-3.5%). Much higher HbF levels (3.8-11.2%) were observed
when a beta-thalassemia allele was present in trans to the HPFH allele.

- Transient Neonatal Cyanosis

A methemoglobinemic variant of fetal hemoglobin, known as Hb FM-Osaka
(H63Y; 142250.0025), was found in a premature Japanese baby with severe
transient neonatal cyanosis (TNCY; 613977) (Hayashi et al., 1980). The
Osaka variant was also found in newborns with cyanosis by Glader et al.
(1989), Urabe et al. (1996), and Prehu et al. (2003). Dainer et al.
(2008) noted that the presence of a tyrosine at codon 63 in Hb FM-Osaka
causes the formation of a covalent link with heme iron, so that the iron
is stabilized in the ferric (3+) form. When this occurs, methemoglobin
is formed, oxygen can no longer bind to heme, and cyanosis occurs.

Glader (1989) identified Hb FM-Fort Ripley, caused by a heterozygous
mutation in the HBG2 gene (H92Y; 142250.0034), in a healthy but cyanotic
newborn girl. The patient reported by Priest et al. (1989) had the Hb
FM-Fort Ripley variant.

In 2 sibs with neonatal transient cyanosis, Dainer et al. (2008)
identified a heterozygous mutation in the HBG2 gene (H63L; 142250.0050),
which was termed Hb F-Circleville. The heterozygous mutation was found
in patient's father, who had no recollection of neonatal cyanosis.
Position his63 in HBG2 coordinates with heme iron and is mutant in Hb
FM-Osaka (H63Y; 142250.0025).

In a female infant with neonatal cyanosis and anemia, Crowley et al.
(2011) identified a heterozygous mutation in the HBG2 gene (V67M;
142250.0051). The variant was named Hb-Toms River. This mutation
modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms.
First, the relatively large side chain of methionine decreases both the
affinity of oxygen for binding to the mutant hemoglobin subunit via
steric hindrance and the rate at which it does so. Second, the mutant
methionine is converted to aspartic acid posttranslationally, probably
through oxidative mechanisms. The presence of this polar amino acid in
the heme pocket was predicted to enhance hemoglobin denaturation,
causing anemia. The patient's father, who was also heterozygous for the
mutation, had transient neonatal cyanosis, which resolved within 1 to 2
months.

*FIELD* AV
.0001
HEMOGLOBIN F (ALBAICIN)
HBG2, LYS8GLX

See de Pablos et al. (1986).

.0002
HEMOGLOBIN F (AUCKLAND)
HBG2, ASP7ASN

See Carrell et al. (1974) and Chen et al. (1985).

.0003
HEMOGLOBIN F (CALTECH)
HBG2, LYS120GLN

See Shelton et al. (1982).

.0004
HEMOGLOBIN F (CARLTON)
HBG2, GLU121LYS

See Brennan et al. (1977).

.0005
HEMOGLOBIN F (CLARKE)
HBG2, LYS65ASN

See Kutlar et al. (1987).

.0006
HEMOGLOBIN F (COLUMBUS-GA)
HBG2, ASP94ASN

See Nakatsuji et al. (1982).

Cherchi et al. (2000) observed Hb F-Columbus-GA in Sardinia where the
variant appeared to be rather frequent in 2 villages.

.0007
HEMOGLOBIN F (FUCHU)
HBG2, GLU21GLN

See Hayashi et al. (1986).

.0008
HEMOGLOBIN F (HEATHER)
HBG2, THR12ARG
.0009
HEMOGLOBIN F (KENNESTONE)
HBG2, HIS77ARG

See Nakatsuji et al. (1983).

.0010
HEMOGLOBIN F (KINGSTON)
HBG2, MET55ARG

See Serjeant et al. (1982).

.0011
HEMOGLOBIN F (LA GRANGE)
HBG2, GLU101LYS

See Nakatsuji et al. (1984).

.0012
HEMOGLOBIN F (LODZ)
HBG2, SER44ARG

See Honig et al. (1982), who described this variant in a newborn of
Polish ancestry. Cepreganova et al. (1991) observed a second example in
a healthy Polish male newborn living in the Atlanta (Ga.) area.

.0013
HEMOGLOBIN F (MALAYSIA)
HBG2, GLY1CYS

See Lie-Injo et al. (1974).

.0014
HEMOGLOBIN F (MALTA)
HBG2, HIS117ARG

See Cauchi et al. (1969) and Mazza et al. (1980).

.0015
HEMOGLOBIN F (MARIETTA)
HBG2, ASP80ASN

See Wrightstone (1982)

.0016
HEMOGLOBIN F (MEINOHAMA)
HBG2, GLU5GLY

See Ohta et al. (1981).

.0017
HEMOGLOBIN F (MELBOURNE)
HBG2, GLY16ARG

See Brennan et al. (1977).

.0018
HEMOGLOBIN F (MINOO)
HBG2, GLY72ARG

See Hayashi et al. (1986).

.0019
HEMOGLOBIN F (OAKLAND)
HBG2, GLU26LYS

See Kleman et al. (1987).

.0020
HEMOGLOBIN F (POOLE)
HBG2, TRP130GLY

See Lee-Potter et al. (1975).

.0021
HEMOGLOBIN F (PORT ROYAL)
HBG2, GLU125ALA

See Brimhall et al. (1974).

.0022
HEMOGLOBIN F (SHANGHAI)
HBG2, LYS66ARG

See Zeng et al. (1985).

.0023
HEMOGLOBIN F (TOKYO)
HBG2, VAL34ILE

See Chen et al. (1985) and Hidaka et al. (1986).

.0024
HEMOGLOBIN F (URUMQI)
HBG2, ASP22GLY

See Hu and Ma (1986).

.0025
CYANOSIS, TRANSIENT NEONATAL
HBG2, HIS63TYR

In a premature baby with severe transient neonatal cyanosis (613977),
Glader et al. (1989) identified a heterozygous his63-to-tyr (H63Y)
substitution in the HBG2 molecule. See also Hayashi et al. (1980). This
mutation is known as hemoglobin FM-Osaka.

Urabe et al. (1996) reported a full-term baby with Hb FM-Osaka who was
cyanotic from birth but did not require special treatment.

Prehu et al. (2003) identified this anomalous hemoglobin in a newborn
male in southwest France who presented at birth with marked cyanosis. He
was of normal weight and was born uneventfully at 41 weeks from a
28-year-old mother. Studies excluded a cardiovascular origin of the
cyanosis, which persisted under oxygen therapy. The intensity of
cyanosis decreased after a few months. The mother had been cyanotic
during her first year of life.

Dainer et al. (2008) identified a mutation affecting this same codon
(H63L; 142250.0050) in 2 sibs with transient neonatal cyanosis. Dainer
et al. (2008) noted that the presence of a tyrosine at codon 63 in Hb
FM-Osaka causes the formation of a covalent link with heme iron, so that
the iron is stabilized in the ferric (3+) form. When this occurs,
methemoglobin is formed, oxygen can no longer bind to heme, and cyanosis
occurs.

.0026
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
HBG2, C-G, -202

As a cause of hereditary persistence of fetal hemoglobin (141749) in the
black population, Collins et al. (1984, 1984, 1985) found a C-to-G
change at nucleotide -202 of the HBG2 gene. This mutation abolished a
normal ApaI restriction endonuclease site and thus could be detected by
blotting of genomic DNA.

.0027
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
HBG2, T-C, -175

Huang et al. (1987) cited 3 types of G-gamma-beta(+)-HPFH: that due to a
C-to-G base substitution at position -202 5-prime to the G-gamma gene;
that due to a T-to-C base substitution at position -175 to this gene;
and the Atlanta type with a G-gamma-G-gamma globin gene arrangement on
one chromosome instead of the normal G-gamma-A-gamma arrangement, with a
C-to-T base substitution at position -158 5-prime to both G-gamma globin
genes. Craig et al. (1993) found the T-to-C mutation at position -175 in
a British family with HPFH (141749). It was first detected by examining
the amplified 5-prime regions of both the G-gamma and A-gamma globin
genes for heteroduplex formation after electrophoresis in a hydrolink
gel.

.0028
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
HBG2, C-T, -158 (dbSNP rs7482144)

This variant, formerly titled HEREDITARY PERSISTENCE OF FETAL
HEMOGLOBIN, has been reclassified based on the findings of Galarneau et
al. (2010).

The -158C-T change in the promoter region of the HBG2 gene is known as
the XmnI-G-gamma polymorphism.

Miller et al. (1987) found a -158C-T transition in the 5-prime promoter
region of the HBG2 gene in individuals with hereditary persistence of
fetal hemoglobin (HPFH; 141749). Their patients, who were from the
eastern province of Saudi Arabia, had sickle cell anemia and high
circulating levels of fetal hemoglobin, 17% HbF on the average, with a
consequently mild form of the disease. The substitution was present in
nearly 100% of patients with sickle cell disease or trait and in 22% of
normal Saudis. Homozygosity for this mutation had no demonstrable effect
on hemoglobin F production in the normal Saudi population.

Garner et al. (2002) identified a quantitative trait locus on chromosome
8q (HBFQTL5; 606789) that interacts with the XmnI-G-gamma site and
influences the production of fetal hemoglobin.

In a cohort of 1,275 African American individuals with sickle cell
disease, Lettre et al. (2008) found that dbSNP rs7482144 can explain
2.2% of the variation in HbF levels. The association could not be tested
in a Brazilian cohort because the variant was monomorphic in this
population.

To fine map HbF association signals at the BCL11A (606557), HBS1L-MYB
(612450-189990), and beta-globin loci, Galarneau et al. (2010)
resequenced 175.2 kb from these loci in 190 individuals including the
HapMap European CEU and Nigerian YRI founders and 70 African Americans
with sickle cell anemia. The authors discovered 1,489 sequence variants,
including 910 previously unreported variants. Using this information and
data from HapMap, Galarneau et al. (2010) selected and genotyped 95
SNPs, including 43 at the beta-globin locus, in 1,032 African Americans
with sickle cell anemia. The XmnI polymorphism dbSNP rs7482144 in the
proximal promoter of HBG2 marks the Senegal and Arab-Indian haplotypes
and is associated with HbF levels in African Americans with sickle cell
disease (Lettre et al., 2008). Galarneau et al. (2010) replicated the
association between dbSNP rs7482144 and HbF levels (p = 3.7 x 10(-7)).
However, dbSNP rs10128556, a T/C SNP located downstream of HBG1
(142200), was more strongly associated with HbF levels than dbSNP
rs7482144 by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned
on dbSNP rs10128556, the HbF association result for dbSNP rs7482144 was
not significant, indicating that dbSNP rs7482144 is not a causal variant
for HbF levels in African Americans with sickle cell anemia. The results
of a haplotype analysis of the 43 SNPs in the beta-globin locus using
dbSNP rs10128556 as a covariate were not significant (p = 0.40),
indicating that dbSNP rs10128556 or a marker in linkage disequilibrium
with it is the principal HbF-influencing variant at the beta-globin
locus in African Americans with sickle cell anemia.

.0029
HEMOGLOBIN F (GRANADA)
HBG2, ASP22VAL

See de Pablos and Clegg (1988).

.0030
HEMOGLOBIN F (AUSTELL)
HBG2, ARG40LYS

See Kutlar et al. (1988).

.0031
HEMOGLOBIN F (BROOKLYN)
HBG2, LYS66GLN

See Plaseska et al. (1990).

.0032
HEMOGLOBIN F (ONODA)
HBG2, HIS146TYR

See Harano et al. (1990).

.0034
CYANOSIS, TRANSIENT NEONATEL
HBG2, HIS92TYR

This fetal hemoglobin M was discovered in a healthy newborn girl with
neonatal cyanosis (613977). By 5 weeks of age she was no longer cyanotic
because gamma-chain synthesis had been replaced by beta-chain synthesis.
See Priest et al. (1989) and Glader (1989). This mutation is known as
hemoglobin FM-Fort Ripley.

.0035
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
HBG2, C-T, -114

Fucharoen et al. (1990) described a C-to-T transition at nucleotide -114
within the distal CCAAT motif of the HBG2 gene as the cause of
hereditary persistence of fetal hemoglobin (141749) in a Japanese
family. They demonstrated that the mutation abolishes the binding of the
ubiquitous CCAAT binding factor CP1, but did not affect the binding of
any erythroid specific factor.

.0036
HEMOGLOBIN F (CATALONIA)
HBG2, TRP15ARG

In 2 Spanish newborn babies from northeastern Spain, Plaseska et al.
(1990) identified a new fetal hemoglobin variant. Whether the
trp15-to-arg mutation had any effect on the functional or histochemical
properties of the fetal hemoglobin had not been determined.

.0037
HEMOGLOBIN F (COSENZA)
HBG2, GLY25GLU

In Cosenza, Italy, Qualtieri et al. (1991) described a fast-moving
gamma-chain variant. Structural analysis showed a gly-to-glu
substitution at position 25 of the G-gamma chain. The propositus was a
healthy newborn.

.0038
HEMOGLOBIN F (SACROMONTE)
HBG2, LYS59GLN

Hb F (Sacromonte) was characterized by sequence analysis of amplified
DNA from a Spanish newborn and his mother (Pobedimskaya et al., 1993).
Both individuals were compound heterozygotes for a previously described
ile75-to-thr (ATA-to-ACA) transition in the gamma-A globin gene and a
novel lys59-to-gln (AAA-to-CAA) mutation in the gamma-G globin gene.
This finding implies that the 2 loci are linked on the same chromosome.

.0039
HEMOGLOBIN F (WAYNESBORO)
HBG2, ILE75THR

Ferranti et al. (1994) found that the cord blood sample of a newborn
contained about 40% of an abnormal fetal hemoglobin. The variant was
found to involve the HBG2 gene and to have a substitution of threonine
for isoleucine at position 75. This is the same substitution as had
previously been described in Hb F (Charlotte) (142200.0032), a mutation
in the HBG1 gene, which has an additional ala136-to-gly substitution.
Indeed, the Caucasian newborn described by Ferranti et al. (1994) was a
double heterozygote for the Hb F (Charlotte) mutation of HBG1 and the
ile75-to-thr mutation of HBG2. Gu et al. (1995) described the
ile75-to-thr mutation of the HBG2 gene in a black newborn from
Waynesboro, Georgia, and called it Hb F-Waynesboro. Only 2 mutations
were observed in the coding regions of the gamma-globin genes in the Hb
F-Waynesboro heterozygotes (the newborn and his mother and brother);
both involved an ATA-to-ACA change at codon 75 of the G-gamma and
A-gamma gene, while codon 136 was GGA (gly) only in the G-gamma gene and
GCA (ala) only in the A-gamma gene. From a comparison with the other
reported cases, Gu et al. (1995) concluded that Hb F-Charlotte is the
product of an A-gamma gene with a limited gene conversion, whereas Hb
F-Waynesboro is the product of a mutated G-gamma gene.

.0040
HEMOGLOBIN F (MACEDONIA II)
HBG2, LYS104ASN

In the course of a newborn screening program for hemoglobinopathies in
Macedonia, Plaseska et al. (1994) detected a lys104-to-asn mutation in
the G-gamma chain resulting from an AAG-to-AAC transversion. The same
mutation was found in the mother and in the healthy newborn. Although
the mutated G was the last nucleotide of exon 2 and part of the donor
splice site sequence of the second intervening sequence of the HBG2
gene, it appeared that the splicing of the mRNA in this variant was not
altered.

.0041
CYANOSIS, TRANSIENT NEONATAL
HBG2, PHE41SER

In a term infant with mild cyanosis without evidence of hypoxia
(613977), Kohli-Kumar et al. (1995) excluded cardiopulmonary disease,
polycythemia, and methemoglobinemia as causes. Standard hemoglobin
electrophoresis, including isoelectric focusing, was normal. However, by
reverse-phase HPLC on a C(4) column, they detected an abnormal globin
chain. Amino acid sequencing revealed a phe41-to-ser (F41S) substitution
in the G-gamma chain. This was confirmed by DNA sequencing that
demonstrated the point mutation at the expected site in exon 2 of the
HBG2 gene. This substitution, designated hemoglobin F-Cincinnati,
presumably decreased oxygen affinity of the hemoglobin. The
corresponding substitution in the beta-globin gene is found in
hemoglobin Denver (HBB; 141900.0441) and is associated with cyanosis.

.0042
HEMOGLOBIN F (EMIRATES)
HBG2, LYS59GLU

In a newborn baby in the United Arab Emirates, Abbes et al. (1995)
identified a rapidly migrating fetal hemoglobin variant and showed by
miniaturized techniques of protein chemistry that the mutation resided
in the G-gamma chain and resulted in a lys59-to-glu substitution. At the
same time, they observed replacement of the same amino acid by glutamine
in Hb F-Sacromonte.

.0043
HEMOGLOBIN F (SACROMONTE)
HBG2, LYS59GLN

In a hematologically normal newborn infant in France, Abbes et al.
(1995) observed a rapidly migrating fetal hemoglobin variant which they
could show carried a change of lysine-59 to glutamine.

.0044
HEMOGLOBIN F (VELETA)
HBG2, ARG40GLY

In a newborn Spanish male, de Pablos Gallego et al. (1995) demonstrated
a new HbF variant and showed that it contained an arg40-to-gly
substitution in the G-gamma chain. The amino acid substitution resulted
from an AGG-to-GGG transition.

.0045
HEMOGLOBIN F (LESVOS)
HBG2, ILE75THR

Papadakis et al. (1996) discovered a new G-gamma chain variant during
globin chain analysis for prenatal diagnosis in a fetus at risk for
beta-thalassemia. The molecular basis was found to be a T-to-C
transition at nucleotide 402 of the HBG2 gene resulting in an
ile75-to-thr substitution. The variant was called Hb F-Lesvos after the
island of origin of the proband.

.0046
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
HBG2, C-A, -114

In an Algerian family with HPFH (141749), Zertal-Zidani et al. (1999)
identified a novel C-to-A transversion at position -114 in the distal
CCAAT box of the G-gamma globin gene promoter. This substitution
cosegregated with a unique beta-globin gene cluster haplotype.
Individuals heterozygous for this mutation exhibited moderate rise in
HbF levels (0.6-3.5%). Much higher HbF levels (3.8-11.2%) were observed
when a beta-thalassemia allele was present in trans to the HPFH allele.

.0047
HEMOGLOBIN F (CALABRIA)
HBG2, PHE118LEU

Manca et al. (2000) found Hb F-Calabria (phe118 to leu; F118L) during
routine screening for abnormal hemoglobins in a newborn of Calabrian
(southern Italy) ancestry. The nucleotide change was a transition
converting codon 118 from TTC to CTC. A molecular modeling study
suggested that the variant might not have clinical implications. The
authors stated that this was the fortieth example of a variant of the
gamma-G chain; in fact, this would appear to be the forty-seventh.

.0048
HEMOGLOBIN F (CLAMART)
HBG2, LYS17ASN

Wajcman et al. (2000) found Hb F-Clamart (lys17 to asn) during
investigation of a French newborn who presented with mild microcytemia.
It is the fetal counterpart of the beta-chain variant, Hb J-Amiens (HBB,
lys17 to asn; 141900.0120). Hb J-Amiens is clinically silent and this
seemed also to be the case for the corresponding fetal variant.

.0049
HEMOGLOBIN F (OULED RABAH)
HBG2, ASN19LYS

Wajcman et al. (2000) found Hb F-Ouled Rabah (asn19 to lys) during
neonatal screening for hemoglobinopathies of 30,000 babies from a
population at risk living in the Paris region. It was named Hb F-Ouled
Rabah because its structural modification and ethnic distribution were
similar to those of Hb D-Ouled Rabah (141900.0064), which shows the same
substitution in the beta-globin gene (HBB, asn19 to lys). Like the
beta-globin variant, Hb F-Ouled Rabah is clinically silent, and occurs
at a frequency of approximately 0.1% in newborns originating from
Maghreb.

.0050
CYANOSIS, TRANSIENT NEONATAL
HBG2, HIS63LEU

In a male newborn with neonatal transient cyanosis and anemia (613977),
Dainer et al. (2008) identified a heterozygous A-T transversion in the
HBG2 gene, resulting in a his63-to-leu (H63L) substitution. They termed
the mutation Hb F-Circleville. Position his63 in HBG2 coordinates with
heme iron and is mutant in Hb FM-Osaka (H63Y; 142250.0025). The
patient's oxygen saturation was 85% on room air and he required
supplemental oxygen. His 4-year-old sister had a similar neonatal course
and had required supplemental oxygen for the first 4 to 5 months of
life, at which time she became asymptomatic. The heterozygous mutation
was found in the sister and father, who had no recollection of neonatal
cyanosis. High performance liquid chromatography showed showed 68.4%
HbF, 17.5% HbA, and 14.0% HbX, eluting between HbF and HbA.
Spectroscopic analysis was not performed. Dainer et al. (2008) noted
that the presence of a tyrosine at codon 63 in Hb FM-Osaka causes the
formation of a covalent link with heme iron, so that the iron is
stabilized in the ferric (3+) form. When this occurs, methemoglobin is
formed, oxygen can no longer bind to heme, and cyanosis occurs.

.0051
CYANOSIS, TRANSIENT NEONATAL
HBG2, VAL67MET

In a female infant with neonatal cyanosis (613977), Crowley et al.
(2011) identified a heterozygous 202G-A transition in the HBG2 gene,
resulting in a val67-to-met (V67M) substitution in the eleventh amino
acid of gamma-globin helix E (E11). The variant was named Hb-Toms River.
The patient also had moderate anemia and reticulocytosis. This mutation
modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms.
First, the relatively large side chain of methionine decreases both the
affinity of oxygen for binding to the mutant hemoglobin subunit via
steric hindrance and the rate at which it does so. Second, the mutant
methionine is converted to aspartic acid posttranslationally, probably
through oxidative mechanisms. The presence of this polar amino acid in
the heme pocket was predicted to enhance hemoglobin denaturation,
causing anemia. The patient's father, who was also heterozygous for the
mutation, had transient neonatal cyanosis, which resolved within 1 to 2
months.

.0052
HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
HBG2, T-G, -567

In an Iranian American father and son with HPFH (141749), Chen et al.
(2008) identified a heterozygous -567T-G transversion within a GATA
motif in a silencing element in the 5-prime region of the HBG2 gene. The
motif is uniquely conserved in simian primates. The mutation was not
found in 300 control individuals. The mutation (GATA-GAGA) disrupted a
GATA1 (305371)-binding domain, resulting in the abolition of its
silencing effect and upregulation of the gamma-globin gene expression in
adults. These findings were confirmed by in vitro studies, which showed
that the mutation increased promoter activity by 2- to 3-fold. The
father and his 9-year-old son had 10.2% and 5.9% HbF, respectively, and
had no clinical symptoms.

*FIELD* SA
Chen et al. (1985); Labie et al. (1985); Plaseska et al. (1990)
*FIELD* RF
1. Abbes, S.; Fitzgerald, P. A.; Varady, E.; Girot, R.; Pic, P.; Blouquit,
Y.; Ducrocq, R.; Drupt, F.; Wajcman, H.: Two fetal hemoglobin variants
affecting the same residue: Hb F-Emirates [G-gamma 59(E3)lys-to-glu]
and Hb F-Sacromonte [G-gamma 59(E3)lys-to-gln]. Hemoglobin 19: 173-182,
1995.

2. Brennan, S. O.; Smith, M. B.; Carrell, R. W.: Haemoglobin F Melbourne
gamma-G 16 gly-to-arg and haemoglobin F Carlton gamma-G 121 glu-to-lys:
further evidence for varied activity of gamma-chain genes. Biochim.
Biophys. Acta 490: 452-455, 1977.

3. Brimhall, B.; Vedvick, T. S.; Jones, R. T.; Ahern, E.; Palomino,
E.; Ahern, V.: Haemoglobin F Port Royal (gamma-2 glu-to-ala). Brit.
J. Haemat. 27: 313-318, 1974.

4. Carrell, R. W.; Owen, M. C.; Anderson, R.; Berry, E.: Haemoglobin
F Auckland (gamma 7 asp-to-asn): further evidence for multiple genes
for the gamma chain. Biochim. Biophys. Acta 365: 323-327, 1974.

5. Carver, M. F. H.; Kutlar, A.: International Hemoglobin Information
Center: variant list. Hemoglobin 19: 37-149, 1995.

6. Cauchi, M. N.; Clegg, J. B.; Weatherall, D. J.: Haemoglobin F
(Malta): a new foetal haemoglobin variant with a high incidence in
Maltese infants. Nature 223: 311-313, 1969.

7. Cepreganova, B.; Gu, L.-H.; Wilson, J. B.; Huisman, T. H. J.:
A second observation of Hb F-Lodz or G-gamma-2 44(CD3)ser-to-arg. Hemoglobin 15:
549-551, 1991.

8. Chen, S. S.; Wilson, J. B.; Webber, B. B.; Huisman, T. H. J.; Miwa,
S.; Amenomori, Y.: Hb F-Tokyo or G-gamma-34(B16)val-to-ile, a silent
gamma chain variant detected by reverse phase high performance liquid
chromatography. Hemoglobin 9: 25-32, 1985.

9. Chen, S. S.; Wilson, J. B.; Webber, B. B.; Kutlar, A.; Huisman,
T. H. J.: Hemoglobin F-Auckland (G-gamma7(A4)asp-to-asn) observed
in a Caucasian newborn from Alabama. Hemoglobin 9: 531-533, 1985.

10. Chen, Z.; Luo, H.-Y.; Basran, R. K.; Hsu, T.-H.; Mang, D. W. H.;
Nuntakarn, L.; Rosenfield, C. G.; Patrinos, G. P.; Hardison, R. C.;
Steinberg, M. H.; Chui, D. H. K.: A T-to-G transversion at nucleotide
-567 upstream of HBG2 in a GATA-1 binding motif is associated with
elevated hemoglobin F. Molec. Cell. Biol. 28: 4386-4393, 2008.

11. Cherchi, L.; Palici di Suni, M.; Manca, L.; Masala, B.: Characterization
by DNA sequencing of Hb F-Columbus-GA [G-gamma-94(FG1)asp-asn] observed
in Sardinian newborn. Hemoglobin 24: 53-57, 2000.

12. Collins, F. S.; Boehm, C. D.; Waber, P. G.; Stoeckert, C. J.,
Jr.; Weissman, S. M.; Forget, B. G.; Kazazian, H. H., Jr.: Concordance
of a point mutation 5-prime to the G-gamma globin gene with G-gamma-beta(+)
hereditary persistence of fetal hemoglobin in the black population. Blood 64:
1292-1296, 1984.

13. Collins, F. S.; Cole, J. L.; Lockwood, W. K.: Expression analysis
of fetal globin gene promoter mutations in hereditary persistence
of fetal hemoglobin. (Abstract) Am. J. Hum. Genet. 37: A149, 1985.

14. Collins, F. S.; Stoeckert, C. J., Jr.; Serjeant, G. R.; Forget,
B. G.; Weissman, S. M.: G-gamma-beta(+) hereditary persistence of
fetal hemoglobin: cosmid cloning and identification of a specific
mutation 5-prime to the G-gamma gene. Proc. Nat. Acad. Sci. 81:
4894-4898, 1984.

15. Comi, P.; Giglioni, B.; Ottolenghi, S.; Barba, P.; Covelli, A.;
Migliaccio, G.; Condorelli, M.; Peschle, C.: Globin chain synthesis
in single erythroid bursts from cord blood: studies on gamma-to-beta
and G-gamma-to-A-gamma switches. Proc. Nat. Acad. Sci. 77: 362-365,
1980.

16. Craig, J. E.; Sheerin, S. M.; Barnetson, R.; Thein, S. L.: The
molecular basis of HPFH in a British family identified by heteroduplex
formation. Brit. J. Haemat. 84: 106-110, 1993.

17. Crowley, M. A.; Mollan, T. L.; Abdulmalik, O. Y.; Butler, A. D.;
Goodwin, E. F.; Sarkar, A.; Stolle, C. A.; Gow, A. J.; Olson, J. S.;
Weiss, M. J.: A hemoglobin variant associated with neonatal cyanosis
and anemia. New Eng. J. Med. 364: 1837-1843, 2011. Note: Erratum:
New Eng. J. Med. 365: 281 only, 2011.

18. Dainer, E.; Shell, R.; Miller, R.; Atkin, J. F.; Pastore, M.;
Kutlar, A.; Zhuang, L.; Holley, L.; Davis, D. H.; Kutlar, F.: Neonatal
cyanosis due to a novel fetal hemoglobin: Hb F-Circleville [G-gamma-63(E7)his-to-leu,
CAT-CTT]. Hemoglobin 32: 596-600, 2008.

19. de Pablos, J. M.; Clegg, J. B.: Hb F-Granada or gamma-G-22 (B4)
asp-to-val: a new human fetal hemoglobin variant. Hemoglobin 12:
405-407, 1988.

20. de Pablos, J. M.; Wilson, J. B.; Kutlar, A.; Chen, S. S.; Huisman,
T. H. J.: Hb F-Albaicin or gamma8 (A5) lys-to-glu or gln. Hemoglobin 10:
655-659, 1986.

21. de Pablos Gallego, J. M.; Gu, L.-H.; Leonova, J. Y.; Huisman,
T. H. J.: Hb F-Veleta or alpha(2)(G-gamma(2)40(C6)arg-to-gly. Hemoglobin 19:
407-411, 1995.

22. Fei, Y. J.; Lanclos, K. D.; Kutlar, F.; Walker, E. L., III; Huisman,
T. H. J.: A chromosome with five gamma-globin genes. Blood 72:
827-829, 1988.

23. Ferranti, P.; Barone, F.; Pucci, P.; Malorni, A.; Marino, G.;
Pilo, G.; Manca, L.; Masala, B.: Hb F-Sassari: a novel G-gamma variant
with a threonine residue at position gamma-75, characterized by mass
spectrometric techniques. Hemoglobin 18: 307-315, 1994.

24. Foley, H. A.; Ofori-Acquah, S. F.; Yoshimura, A.; Critz, S.; Baliga,
B. S.; Pace, B. S.: Stat-3 beta inhibits gamma-globin gene expression
in erythroid cells. J. Biol. Chem. 277: 16211-16219, 2002.

25. Fritsch, E. F.; Lawn, R. M.; Maniatis, T.: Molecular cloning
and characterization of the human beta-like globin gene cluster. Cell 19:
959-972, 1980.

26. Fucharoen, S.; Shimizu, K.; Fukumaki, Y.: A novel C-to-T transition
within the distal CCAAT motif of the G-gamma-globin gene in the Japanese
HPFH: implication of factor binding in elevated fetal globin expression. Nucleic
Acids Res. 18: 5245-5253, 1990.

27. Galarneau, G.; Palmer, C. D.; Sankaran, V. G.; Orkin, S. H.; Hirschhorn,
J. N.; Lettre, G.: Fine-mapping at three loci known to affect fetal
hemoglobin levels explains additional genetic variation. Nature Genet. 42:
1049-1051, 2010.

28. Garner, C. P.; Tatu, T.; Best, S.; Creary, L.; Thein, S. L.:
Evidence of genetic interaction between the beta-globin complex and
chromosome 8q in the expression of fetal hemoglobin. Am. J. Hum.
Genet. 70: 793-799, 2002.

29. Glader, B. E.: Hemoglobin, FM-Fort Ripley: another lesson from
the neonate. Pediatrics 83: 792-793, 1989.

30. Glader, B. E.; Zwerdling, D.; Kutlar, F.; Kutlar, A.; Wilson,
J. B.; Huisman, T. H. J.: Hb F-M-Osaka or gamma63(E7)his-to-tyr in
a Caucasian male infant. Hemoglobin 13: 769-773, 1989.

31. Gu, L.-H.; Oner, C.; Huisman, T. H. J.: The G-gamma-T chain (G-gamma-75
THR; 136 GLY) in Hb F-Charlotte is the product of an A-gamma gene
with a limited gene conversion and that in Hb F-Waynesboro of a mutated
G-gamma gene. Hemoglobin 19: 413-418, 1995.

32. Harano, T.; Harano, K.; Doi, K.; Ueda, S.; Imai, K.; Ohba, Y.;
Kutlar, F.; Huisman, T. H. J.: Hb F-Onoda or gamma146(HC3)his-to-tyr,
a newly discovered fetal hemoglobin variant in a Japanese newborn. Hemoglobin 14:
217-222, 1990.

33. Hayashi, A.; Fujita, T.; Fujimura, M.; Titani, K.: A new abnormal
fetal hemoglobin, Hb FM-Osaka (gamma 63 his-to-tyr). Hemoglobin 4:
447-448, 1980.

34. Hayashi, A.; Wada, Y.; Matsuo, T.; Katakuse, I.; Matsuda, H.:
Neonatal screening and mass spectrometric analysis of haemoglobin
variants in Japan. (Abstract) Haemoglobin Research and Applications
Symposium, England , 1986.

35. Hidaka, K.; Iuchi, I.; Kimu, K.; Morita, T.: Hb F-Tokyo or G-gamma34
val-to-ile found in a newborn baby in Japan. Hemoglobin 10: 529-532,
1986.

36. Honig, G. R.; Koshy, M.; Schroeder, W. A.; Shelton, J. B.; Shelton,
J. R.: Hemoglobin F Lodz (G-gamma-I 44 ser-to-arg): a newly identified
variant from an American infant of Polish descent. Biochim. Biophys.
Acta 707: 213-216, 1982.

37. Hu, H.; Ma, M.: Hb F-Urumqi, G-gamma-I 22 (B4) asp-to-gly: a
new fetal hemoglobin variant found in a Uygur baby. Hemoglobin 10:
15-20, 1986.

38. Huang, H. J.; Stoming, T. A.; Harris, H. F.; Kutlar, F.; Huisman,
T. H. J.: The Greek A-gamma-beta+/HPFH observed in a large black
family. Am. J. Hemat. 25: 401-408, 1987.

39. Huisman, T. H. J.; Schroeder, W. A.; Bannister, W. H.; Grech,
J. L.: Evidence for four nonallelic structural genes for the gamma
chain of human fetal hemoglobin. Biochem. Genet. 7: 131-139, 1972.

40. Kleman, K.; Lubin, B.; Wilson, J. B.; Kutlar, A.; Webber, B. B.;
Huisman, T. H. J.: Hb F-Oakland or G-gamma-I-26 (B8) glu-to-lys. Hemoglobin 11:
181-183, 1987.

41. Kohli-Kumar, M.; Zwerdling, T.; Rucknagel, D. L.: Hb F-Cincinnati,
alpha-2-G-gamma-2-41(C7) phe-to-ser in a newborn with cyanosis. Am.
J. Hemat. 49: 43-47, 1995.

42. Kutlar, A.; Kutlar, F.; Wilson, J. B.; Webber, B. B.; Gonzalez-Redondo,
J. M.; Huisman, T. H. J.: Hb F-Clarke or G-gamma-65 (E9) lys-to-asn. Hemoglobin 11:
185-188, 1987.

43. Kutlar, A.; Kutlar, F.; Wilson, J. B.; Webber, B. B.; Hu, H.;
Huisman, T. H. J.: Hb F-Austell or G-gamma-40 (C6) arg-to-lys. Hemoglobin 12:
409-411, 1988.

44. Labie, D.; Pagnier, J.; Lapoumeroulie, C.; Rouabhi, F.; Dunda-Belkhodja,
O.; Chardin, P.; Beldjord, C.; Wajcman, H.; Fabry, M. E.; Nagel, R.
L.: Common haplotype dependency of high G-gamma-globin gene expression
and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc.
Nat. Acad. Sci. 82: 2111-2114, 1985.

45. Lee-Potter, J. P.; Deacon-Smith, R. A.; Simpkiss, M. J.; Kamuzora,
H.; Lehmann, H.: A new cause of haemolytic anemia in the newborn:
a description of an unstable fetal haemoglobin: F Poole, G-gamma 130
trp-to-gly. J. Clin. Path. 28: 317-320, 1975.

46. Lettre, G.; Sankaran, V. G.; Bezerra, M. A. C.; Araujo, A. S.;
Uda, M.; Sanna, S.; Cao, A.; Schlessinger, D.; Costa, F. F.; Hirschhorn,
J. N.: Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB,
and beta-globin loci associate with fetal hemoglobin levels and pain
crises in sickle cell disease. Proc. Nat. Acad. Sci. 105: 11869-11874,
2008.

47. Lie-Injo, L. E.; Kamuzora, H.; Lehmann, H.: Haemoglobin F (Malaysia)
gamma 1 (NA1) glycine-to-cysteine; 136 glycine. J. Med. Genet. 11:
25-30, 1974.

48. Manca, L.; Cherchi, L.; De Rosa, M. C.; Giardina, B.; Masala,
B.: A new, electrophoretically silent, fetal hemoglobin variant:
Hb F-Calabria [G-gamma-118(GH1)phe-leu]. Hemoglobin 24: 37-44, 2000.

49. Mazza, U.; Meloni, T.; David, O.; Pich, P. G.; Camaschella, C.;
Saglio, G.; Vasino, M. A. C.; Guerrasio, A.; Ricco, G.: Gamma chain
composition in five Italian newborns heterozygous for Hb F Malta. Brit.
J. Haemat. 44: 93-99, 1980.

50. Metherall, J. E.; Gillespie, F. P.; Forget, B. G.: Analyses of
linked beta-globin genes suggest that nondeletion forms of hereditary
persistence of fetal hemoglobin are bona fide switching mutants. Am.
J. Hum. Genet. 42: 476-481, 1988.

51. Miller, B. A.; Olivieri, N.; Salameh, M.; Ahmed, M.; Antognetti,
G.; Huisman, T. H. J.; Nathan, D. G.; Orkin, S. H.: Molecular analysis
of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia. New
Eng. J. Med. 316: 244-250, 1987.

52. Nakatsuji, T.; Lam, H.; Huisman, T. H. J.: Hb F-Kennestone or
alpha(2)G-gamma(2) (EF1)77 his-to-arg observed in a Caucasian baby. Hemoglobin 7:
267-270, 1983.

53. Nakatsuji, T.; Lam, H.; Wilson, J. B.; Webber, B. B.; Huisman,
T. H. J.: Hb F-Columbus-Ga or G-gamma94 (FG1) asp-to-asn. Hemoglobin 6:
593-598, 1982.

54. Nakatsuji, T.; Shimizu, K.; Huisman, T. H. J.: Hb F-La Grange
or gamma101(G3)glu-to-lys; 75Ile; 136Gly: a high oxygen affinity fetal
hemoglobin variant observed in a Caucasian newborn. Biochim. Biophys.
Acta 789: 224-228, 1984.

55. Ohta, Y.; Saito, S.; Fujita, S.; Wilson, J. B.; Lam, H.; Huisman,
T. H. J.: Hb F-Meinohama or alpha(2)gamma(2) (5 glu-to-gly; 75Ile;
136 gly). Hemoglobin 5: 565-570, 1981.

56. Old, J.; Clegg, J. B.; Ottolenghi, S.; Comi, P.; Giglioni, B.;
Mitchell, J.; Tolstoshev, P.; Williamson, R.: A direct estimate of
the number of human gamma-globin genes. Cell 8: 13-18, 1976.

57. Papadakis, M. N.; Patrinos, G. P.; Drakoulakou, O.; Loutradi-Anagnostou,
A.: HbF-Lesvos: an HbF variant due to a novel G-gamma mutation (:G(gamma)
75 ATA-to-ACA) detected in a Greek family. Hum. Genet. 97: 260-262,
1996.

58. Plaseska, D.; Li, H.-J.; Wilson, J. B.; Kutlar, F.; Kutlar, A.;
Huisman, T. H. J.; Kulpa, J.: Hb F-Brooklyn or G-gamma66(E10)lys-to-gln. Hemoglobin 14:
213-216, 1990.

59. Plaseska, D.; Panovska-Popovska, S.; Lazarevski, M.; Efremov,
G. D.: Hb F-Macedonia-II (G-gamma104(G6)lys-to-asn): a new gamma
chain variant. Hemoglobin 18: 373-382, 1994.

60. Plaseska, D.; Wilson, J. B.; Kutlar, F.; Font, L.; Baiget, M.;
Huisman, T. H. J.: Hb F-Catalonia or G-gamma-15(A12)trp-to-arg. Hemoglobin 14:
511-516, 1990.

61. Pobedimskaya, D. D.; Molchanova, T. P.; Gu, L.-H.; Molina, M.
A.; de Pablos, J. M.; Huisman, T. H. J.: Hb F-Sacromonte or gamma-G59
(E3) lys-to-gln observed in a Spanish newborn and his mother. Hemoglobin 17:
269-274, 1993.

62. Prehu, C.; Rhabbour, M.; Netter, J. C.; Denier, M.; Riou, J.;
Galacteros, F.; Wajcman, H.: Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr]
in a newborn from southwest France. Hemoglobin 27: 27-30, 2003.

63. Priest, J. R.; Watterson, J.; Jones, R. T.; Faassen, A. E.; Hedlund,
B. E.: Mutant fetal hemoglobin causing cyanosis in a newborn. Pediatrics 83:
734-736, 1989.

64. Qualtieri, A.; Crescibene, L.; Bagala, A.; De Marco, E. V.; Bria,
M.; Brancati, C.: Hb F-Cosenza or G-gamma-25(B7)gly-to-glu: a new
fast-moving fetal hemoglobin variant. Hemoglobin 15: 509-515, 1991.

65. Schroeder, W. A.; Huisman, T. H. J.; Shelton, J. R.; Shelton,
J. B.; Kleihauer, E. F.; Dozy, A. M.; Robberson, B.: Evidence for
multiple structural genes for the gamma chain of human fetal hemoglobin. Proc.
Nat. Acad. Sci. 60: 537-544, 1968.

66. Serjeant, G. R.; Serjeant, B. E.; Lehmann, H.; Dukes, M.; Robb,
L.: Hb F Kingston (G-gamma55 (D6) met-to-arg). FEBS Lett. 150:
77-80, 1982.

67. Shelton, J. B.; Shelton, J. R.; Espinueva, Z.; Huynh, V.; Schroeder,
W. A.; Powars, D.: Hemoglobin F-Caltech: G-gamma120 lys-to-gln. Hemoglobin 6:
577-592, 1982.

68. Thein, S. L.; Hill, F. G. H.; Weatherall, D. J.: Haematological
phenotype of the triplicated gamma-globin gene arrangement. Brit.
J. Haemat. 57: 349-351, 1984.

69. Trent, R. J.; Bowden, D. K.; Old, J. M.; Wainscoat, J. S.; Clegg,
J. B.; Weatherall, D. J.: A novel rearrangement of the human beta-like
globin gene cluster. Nucleic Acids Res. 9: 6723-6733, 1981.

70. Urabe, D.; Li, W.; Hattori, Y.; Ohba, Y.: A new case of Hb F-M-Osaka
[G-gamma-63(E7)his-to-tyr] showed only benign neonatal cyanosis. Hemoglobin 20:
169-173, 1996.

71. Wajcman, H.; Borensztajn, K.; Riou, J.; Prome, D.; Hurtrel, D.;
Bardakdjian, J.; Lena-Russo, D.; Amouroux, I.; Ducrocq, R.: Two new
G-gamma chain variants: Hb F-Clamart [gamma-17(A14)lys-asn] and Hb
F-Ouled Rabah [gamma-19(B1)asn-lys]. Hemoglobin 24: 45-52, 2000.

72. Wrightstone, R. N.: Personal Communication. Atlanta, Ga. 1982.

73. Zeng, Y.-T.; Huang, S. Z.; Nakatsuji, T.; Huisman, T. H. J.:
G-gamma-A-gamma-thalassemia and gamma-chain variants in Chinese newborn
babies. Am. J. Hemat. 18: 235-242, 1985.

74. Zertal-Zidani, S.; Merghoub, T.; Ducrocq, R.; Gerard, N.; Satta,
D.; Krishnamoorthy, R.: A novel C-to-A transversion within the distal
CCAAT motif of the G-gamma-globin gene in the Algerian G-gamma-beta(+)-hereditary
persistence of fetal hemoglobin. Hemoglobin 23: 159-169, 1999.

*FIELD* CN
Cassandra L. Kniffin - updated: 8/2/2011
Anne M. Stumpf: 7/18/2011
Cassandra L. Kniffin - updated: 5/27/2011
Cassandra L. Kniffin - updated: 6/3/2009
Victor A. McKusick - updated: 4/17/2003
Patricia A. Hartz - updated: 5/15/2002
Victor A. McKusick - updated: 3/22/2002
Victor A. McKusick - updated: 5/1/2000
Wilson H. Y. Lo - updated: 7/26/1999

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

*FIELD* ED
wwang: 08/05/2011
ckniffin: 8/2/2011
carol: 8/2/2011
alopez: 7/18/2011
carol: 5/19/2011
carol: 5/17/2011
ckniffin: 5/17/2011
carol: 6/4/2009
ckniffin: 6/3/2009
terry: 12/17/2007
alopez: 10/23/2007
tkritzer: 4/30/2003
terry: 4/17/2003
carol: 5/15/2002
mgross: 3/25/2002
terry: 3/22/2002
mcapotos: 5/31/2000
mcapotos: 5/26/2000
mcapotos: 5/24/2000
terry: 5/1/2000
carol: 4/17/2000
carol: 7/26/1999
terry: 6/18/1998
alopez: 8/1/1997
terry: 7/10/1997
terry: 11/18/1996
mark: 2/26/1996
terry: 2/19/1996
mark: 2/16/1996
mark: 2/13/1996
mark: 2/10/1996
terry: 2/5/1996
mark: 1/5/1996
terry: 1/4/1996
mark: 11/6/1995
carol: 7/9/1995
mimadm: 9/24/1994
jason: 7/29/1994
pfoster: 4/21/1994
carol: 12/13/1993

MIM 613977
*RECORD*
*FIELD* NO
613977
*FIELD* TI
#613977 CYANOSIS, TRANSIENT NEONATAL; TNCY
*FIELD* TX
A number sign (#) is used with this entry because transient neonatal
read morecyanosis is caused by heterozygous mutation in the HBG2 gene (142250) on
chromosome 11p15.5.

DESCRIPTION

Neonatal cyanosis is characterized by symptoms in the fetus and neonate
that gradually abate by 5 to 6 months of age. The disorder is caused by
a defect in the fetal hemoglobin chain, which causes reduced affinity
for oxygen due to steric inhibition of oxygen binding and/or due to
increased oxidation of the fetal hemoglobin molecule to methemoglobin
(Hb FM), which has decreased oxygen-binding capacity. Some patients
develop anemia resulting from increased destruction of red cells
containing abnormal or unstable hemoglobin. The cyanosis resolves
spontaneously by 5 to 6 months of age or earlier, as the adult
beta-globin chain (HBB; 141900) is produced and replaces the fetal
gamma-globin chain (summary by Crowley et al., 2011).

CLINICAL FEATURES

Hayashi et al. (1980) reported a premature Japanese baby with severe
cyanosis and jaundice.

Priest et al. (1989) reported a well newborn who was cyanotic at birth.
He was found to have a mutant gamma-globin chain, leading to
functionally abnormal fetal hemoglobin. This patient showed no clinical
evidence of cyanosis at 5 weeks of age as gamma-chain synthesis was
replaced by beta-chain synthesis. A sib born 20 months later was also
affected.

Urabe et al. (1996) described a full-term baby who was cyanotic from
birth but did not require special treatment.

Prehu et al. (2003) reported a newborn male in southwest France who
presented at birth with marked cyanosis. He was of normal weight and was
born uneventfully at 41 weeks from a 28-year-old mother. Studies
excluded a cardiovascular origin of the cyanosis, which persisted under
oxygen therapy. The intensity of cyanosis decreased after a few months.

Dainer et al. (2008) reported a male with neonatal cyanosis. The
patient's oxygen saturation was 85% on room air and he required
supplemental oxygen. His 4-year-old sister had a similar neonatal course
and had required supplemental oxygen for the first 4 to 5 months of
life, at which time she became asymptomatic. High performance liquid
chromatography of the male infant's blood showed 68.4% HbF, 17.5% HbA,
and 14.0% HbX, eluting between HbF and HbA. Spectroscopic analysis was
not performed.

Crowley et al. (2011) reported a female infant with cyanosis and
moderate hepatomegaly at birth. Hemoglobin oxygen saturation in ambient
air was 30 to 50%. She also had moderate anemia with reticulocytosis,
but methemoglobin levels were normal. Electrophoresis showed that total
hemoglobin consisted of about 90% HbF and 10% HbA, with no variant
bands. She received transfusions, which raised the hemoglobin oxygen
saturation levels. By 2 months of age, her hemoglobin oxygen saturation
was consistently higher than 95%. The patient's father also had
transient neonatal cyanosis, which resolved within 1 to 2 months.

MOLECULAR GENETICS

A methemoglobinemic (M) variant of fetal hemoglobin (HbF), known as Hb
FM-Osaka (H63Y; 142250.0025), was found in a premature Japanese baby
with severe jaundice and cyanosis (Hayashi et al., 1980). The Osaka
variant was also found in newborns with cyanosis by Glader et al.
(1989), Urabe et al. (1996), and Prehu et al. (2003).

Glader (1989) identified Hb FM-Fort Ripley, caused by a heterozygous
mutation in the HBG2 gene (H92Y; 142250.0034), in a healthy but cyanotic
newborn girl. The patient reported by Priest et al. (1989) had the Hb
FM-Fort Ripley variant.

Kohli-Kumar et al. (1995) reported a term infant with mild cyanosis.
Standard hemoglobin electrophoresis, including isoelectric focusing, was
normal. However, by reverse-phase HPLC on a C(4) column, they detected
an abnormal globin chain. Amino acid and DNA sequencing revealed a
heterozygous F41S (142250.0041) substitution in the HBG2 chain. This
substitution, designated hemoglobin F-Cincinnati, presumably decreased
oxygen affinity of the hemoglobin. The corresponding substitution in the
beta-globin gene is found in hemoglobin Denver (HBB; 141900.0441) and is
associated with cyanosis.

In 2 sibs with neonatal transient cyanosis, Dainer et al. (2008)
identified a heterozygous mutation in the HBG2 gene (H63L; 142250.0050),
which was termed Hb F-Circleville. The heterozygous mutation was found
in the father, who had no recollection of neonatal cyanosis. Position
his63 in HBG2 coordinates with heme iron and is mutant in Hb FM-Osaka
(H63Y; 142250.0025). Dainer et al. (2008) noted that the presence of a
tyrosine at codon 63 in Hb FM-Osaka causes the formation of a covalent
link with heme iron, so that the iron is stabilized in the ferric (3+)
form. When this occurs, methemoglobin is formed, oxygen can no longer
bind to heme, and cyanosis occurs.

In a female infant with neonatal cyanosis and anemia, Crowley et al.
(2011) identified a heterozygous mutation in the HBG2 gene (V67M;
142250.0051). The variant was named Hb-Toms River. This mutation
modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms.
First, the relatively large side chain of methionine decreases both the
affinity of oxygen for binding to the mutant hemoglobin subunit via
steric hindrance and the rate at which it does so. Second, the mutant
methionine is converted to aspartic acid posttranslationally, probably
through oxidative mechanisms. The presence of this polar amino acid in
the heme pocket was predicted to enhance hemoglobin denaturation,
causing anemia. The patient's father, who was also heterozygous for the
mutation, had transient neonatal cyanosis, which resolved within 1 to 2
months.

*FIELD* RF
1. Crowley, M. A.; Mollan, T. L.; Abdulmalik, O. Y.; Butler, A. D.;
Goodwin, E. F.; Sarkar, A.; Stolle, C. A.; Gow, A. J.; Olson, J. S.;
Weiss, M. J.: A hemoglobin variant associated with neonatal cyanosis
and anemia. New Eng. J. Med. 364: 1837-1843, 2011. Note: Erratum:
New Eng. J. Med. 365: 281 only, 2011.

2. Dainer, E.; Shell, R.; Miller, R.; Atkin, J. F.; Pastore, M.; Kutlar,
A.; Zhuang, L.; Holley, L.; Davis, D. H.; Kutlar, F.: Neonatal cyanosis
due to a novel fetal hemoglobin: Hb F-Circleville [G-gamma-63(E7)his-to-leu,
CAT-CTT]. Hemoglobin 32: 596-600, 2008.

3. Glader, B. E.: Hemoglobin, FM-Fort Ripley: another lesson from
the neonate. Pediatrics 83: 792-793, 1989.

4. Glader, B. E.; Zwerdling, D.; Kutlar, F.; Kutlar, A.; Wilson, J.
B.; Huisman, T. H. J.: Hb F-M-Osaka or gamma63(E7)his-to-tyr in a
Caucasian male infant. Hemoglobin 13: 769-773, 1989.

5. Hayashi, A.; Fujita, T.; Fujimura, M.; Titani, K.: A new abnormal
fetal hemoglobin, Hb FM-Osaka (gamma 63 his-to-tyr). Hemoglobin 4:
447-448, 1980.

6. Kohli-Kumar, M.; Zwerdling, T.; Rucknagel, D. L.: Hb F-Cincinnati,
alpha-2-G-gamma-2-41(C7) phe-to-ser in a newborn with cyanosis. Am.
J. Hemat. 49: 43-47, 1995.

7. Prehu, C.; Rhabbour, M.; Netter, J. C.; Denier, M.; Riou, J.; Galacteros,
F.; Wajcman, H.: Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr] in a newborn
from southwest France. Hemoglobin 27: 27-30, 2003.

8. Priest, J. R.; Watterson, J.; Jones, R. T.; Faassen, A. E.; Hedlund,
B. E.: Mutant fetal hemoglobin causing cyanosis in a newborn. Pediatrics 83:
734-736, 1989.

9. Urabe, D.; Li, W.; Hattori, Y.; Ohba, Y.: A new case of Hb F-M-Osaka
[G-gamma-63(E7)his-to-tyr] showed only benign neonatal cyanosis. Hemoglobin 20:
169-173, 1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

ABDOMEN:
[Liver];
Hepatomegaly (in some)

SKIN, NAILS, HAIR:
[Skin];
Cyanosis;
Jaundice (in some)

HEMATOLOGY:
Decreased oxygen-binding capacity of hemoglobin;
Decreased hemoglobin oxygen saturation;
Anemia (in some);
Reticulocytosis (in some)

LABORATORY ABNORMALITIES:
Methemoglobinemia

MISCELLANEOUS:
Onset at birth;
Spontaneously resolves by 5 to 6 months of age

MOLECULAR BASIS:
Caused by mutation in the gamma G hemoglobin gene (HBG2, 142250.0025)

*FIELD* CD
Cassandra L. Kniffin: 5/17/2011

*FIELD* ED
joanna: 05/19/2011
ckniffin: 5/17/2011

*FIELD* CD
Cassandra L. Kniffin: 5/16/2011

*FIELD* ED
carol: 08/02/2011
carol: 5/17/2011
ckniffin: 5/17/2011