HGNC Approved Gene Symbol:HBG2
Cytogenetic location:11p15.4 Genomic coordinates(GRCh38) :11:5,253,188-5,254,781 (from NCBI)
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).
Fritsch et al. (1980) isolated clones corresponding to the HBG1 and HBG2 genes as part of the beta-like globin gene cluster (HBB;141900).
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.
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, see142200.
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.
Masuda et al. (2016) found that the LRF/ZBTB7A transcription factor (605878) occupies fetal gamma-globin genes and maintains the nucleosome density necessary for gamma-globin gene silencing in adults. LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A (606557). Knockout of LRF in immortalized adult human erythroid cells resulted in HbF levels of greater than 60% compared with less than 3% in untreated parental cells.
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 byThein 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.
Martyn et al. (2018) carried out an in vitro screen for candidate repressors of the gamma-globin gene and found that BCL11A and ZBTB7A bound to sites -115 bp and -200 bp upstream of the transcription start site in the gamma-globin gene promoter, respectively, in electrophoretic mobility shift assays. All tested HPFH-associated gamma-globin promoter point mutations disrupted binding with BCL11A and ZBTB7A. CRISPR-Cas9 genome editing and chromatin immunoprecipitation studies in human erythroid cells showed that BCL11A and ZBTB7A bound to their respective sites in the gamma-globin gene promoter in vivo and that HPFH-associated mutations in the gamma-globin promoter disrupted in vivo binding and raised gamma-globin gene expression.
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 byGlader et al. (1989),Urabe et al. (1996), andPrehu 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 byPriest 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.
Cherchi et al. (2000) observed Hb F-Columbus-GA in Sardinia where the variant appeared to be rather frequent in 2 villages.
SeeHonig 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.
SeeHu and Ma (1986).
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 alsoHayashi 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.
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.
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.
This variant, formerly titled HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN, has been reclassified based on the findings ofGalarneau 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 thatrs7482144 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 polymorphismrs7482144 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 betweenrs7482144 and HbF levels (p = 3.7 x 10(-7)). However,rs10128556, a T/C SNP located downstream of HBG1 (142200), was more strongly associated with HbF levels thanrs7482144 by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned onrs10128556, the HbF association result forrs7482144 was not significant, indicating thatrs7482144 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 usingrs10128556 as a covariate were not significant (p = 0.40), indicating thatrs10128556 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.
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. SeePriest et al. (1989) andGlader (1989). This mutation is known as hemoglobin FM-Fort Ripley.
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.
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.
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.
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.
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 byFerranti 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.
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.
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.
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.
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.
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.
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.
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.
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.
Wajcman et al. (2000) found Hb F-Clamart (lys17 to asn) during investigation of a French newborn who presented with mild microcythemia. 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.
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.
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 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.
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.
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.
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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. [PubMed:3401603,related citations]
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. [PubMed:7852085,related citations] [Full Text]
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. [PubMed:11856732,related citations] [Full Text]
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. [PubMed:6155216,related citations] [Full Text]
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. [PubMed:1698280,related citations] [Full Text]
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. [PubMed:21057501,related citations] [Full Text]
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. [PubMed:11822023,images,related citations] [Full Text]
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. [PubMed:2483933,related citations] [Full Text]
Glader, B. E.Hemoglobin, FM-Fort Ripley: another lesson from the neonate. Pediatrics 83: 792-793, 1989. [PubMed:2470018,related citations]
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. [PubMed:8718701,related citations] [Full Text]
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. [PubMed:1703139,related citations] [Full Text]
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. [PubMed:6158500,related citations] [Full Text]
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.
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. [PubMed:2430914,related citations] [Full Text]
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. [PubMed:6814491,related citations] [Full Text]
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. [PubMed:2420748,related citations] [Full Text]
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. [PubMed:2441598,related citations] [Full Text]
Huisman, T. H. J., Carver, M. F. H., Efremov, G. D.A Syllabus of Human Hemoglobin Variants (1996). Agusta, Ga.: The Sickle Cell Anemia Foundation 1996.
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. [PubMed:5050916,related citations] [Full Text]
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. [PubMed:2442122,related citations] [Full Text]
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. [PubMed:7741137,related citations] [Full Text]
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. [PubMed:2442123,related citations] [Full Text]
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. [PubMed:2459083,related citations] [Full Text]
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. [PubMed:2580306,related citations] [Full Text]
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. [PubMed:1127124,related citations] [Full Text]
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. [PubMed:18667698,related citations] [Full Text]
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. [PubMed:4837284,related citations] [Full Text]
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. [PubMed:10722114,related citations] [Full Text]
Martyn, G. E., Wienert, B., Yang, L., Shah, M., Norton, L. J., Burdach, J., Kurita, R., Nakamura, Y., Pearson, R. C. M., Funnell, A. P. W., Quinlan, K. G. R., Crossley, M.Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nature Genet. 50: 498-503, 2018. [PubMed:29610478,related citations] [Full Text]
Masuda, T., Wang, X., Maeda, M., Canver, M. C., Sher, F., Funnell, A. P. W., Fisher, C., Suciu, M., Martyn, G. E., Norton, L. J., Zhu, C., Kurita, R., Nakamura, Y., Xu, J., Higgs, D. R., Crossley, M., Bauer, D. E., Orkin, S. H., Kharchenko, P. V., Maeda, T.Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 351: 285-289, 2016. [PubMed:26816381,images,related citations] [Full Text]
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. [PubMed:6155133,related citations] [Full Text]
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. [PubMed:2450454,related citations]
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. [PubMed:2432426,related citations] [Full Text]
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. [PubMed:6192110,related citations] [Full Text]
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. [PubMed:6186636,related citations] [Full Text]
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. [PubMed:6206897,related citations] [Full Text]
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. [PubMed:6172403,related citations] [Full Text]
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. [PubMed:954089,related citations] [Full Text]
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. [PubMed:8566966,related citations] [Full Text]
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. [PubMed:1703138,related citations] [Full Text]
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. [PubMed:7713741,related citations] [Full Text]
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. [PubMed:1706691,related citations] [Full Text]
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. [PubMed:7687241,related citations] [Full Text]
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. [PubMed:12603090,related citations] [Full Text]
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. [PubMed:2470017,related citations]
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. [PubMed:1726095,related citations] [Full Text]
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. [PubMed:5248810,related citations] [Full Text]
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. [PubMed:6186522,related citations] [Full Text]
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. [PubMed:6186635,related citations] [Full Text]
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. [PubMed:6733050,related citations] [Full Text]
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. [PubMed:6174945,related citations] [Full Text]
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. [PubMed:8811323,related citations] [Full Text]
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. [PubMed:10722115,related citations] [Full Text]
Wrightstone, R. N.Personal Communication. Atlanta, Ga. 1982.
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. [PubMed:2579547,related citations] [Full Text]
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. [PubMed:10335983,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: HBG2
SNOMEDCT: 191201002; ICD10CM: D56.4;
Cytogenetic location: 11p15.4 Genomic coordinates(GRCh38) : 11:5,253,188-5,254,781(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Cyanosis, transient neonatal | 613977 | Autosomal dominant | 3 |
| Fetal hemoglobin quantitative trait locus 1 | 141749 | Autosomal dominant | 3 |
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).
Fritsch et al. (1980) isolated clones corresponding to the HBG1 and HBG2 genes as part of the beta-like globin gene cluster (HBB; 141900).
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.
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.
Masuda et al. (2016) found that the LRF/ZBTB7A transcription factor (605878) occupies fetal gamma-globin genes and maintains the nucleosome density necessary for gamma-globin gene silencing in adults. LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A (606557). Knockout of LRF in immortalized adult human erythroid cells resulted in HbF levels of greater than 60% compared with less than 3% in untreated parental cells.
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.
Martyn et al. (2018) carried out an in vitro screen for candidate repressors of the gamma-globin gene and found that BCL11A and ZBTB7A bound to sites -115 bp and -200 bp upstream of the transcription start site in the gamma-globin gene promoter, respectively, in electrophoretic mobility shift assays. All tested HPFH-associated gamma-globin promoter point mutations disrupted binding with BCL11A and ZBTB7A. CRISPR-Cas9 genome editing and chromatin immunoprecipitation studies in human erythroid cells showed that BCL11A and ZBTB7A bound to their respective sites in the gamma-globin gene promoter in vivo and that HPFH-associated mutations in the gamma-globin promoter disrupted in vivo binding and raised gamma-globin gene expression.
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.
See de Pablos et al. (1986).
See Carrell et al. (1974) and Chen et al. (1985).
See Shelton et al. (1982).
See Brennan et al. (1977).
See Kutlar et al. (1987).
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.
See Hayashi et al. (1986).
See Huisman et al. (1996).
See Nakatsuji et al. (1983).
See Serjeant et al. (1982).
See Nakatsuji et al. (1984).
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.
See Lie-Injo et al. (1974).
See Cauchi et al. (1969) and Mazza et al. (1980).
See Wrightstone (1982)
See Ohta et al. (1981).
See Brennan et al. (1977).
See Hayashi et al. (1986).
See Kleman et al. (1987).
See Lee-Potter et al. (1975).
See Brimhall et al. (1974).
See Zeng et al. (1985).
See Chen et al. (1985) and Hidaka et al. (1986).
See Hu and Ma (1986).
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.
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.
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.
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 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 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 rs7482144 and HbF levels (p = 3.7 x 10(-7)). However, rs10128556, a T/C SNP located downstream of HBG1 (142200), was more strongly associated with HbF levels than rs7482144 by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned on rs10128556, the HbF association result for rs7482144 was not significant, indicating that 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 rs10128556 as a covariate were not significant (p = 0.40), indicating that 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.
See de Pablos and Clegg (1988).
See Kutlar et al. (1988).
See Plaseska et al. (1990).
See Harano et al. (1990).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Wajcman et al. (2000) found Hb F-Clamart (lys17 to asn) during investigation of a French newborn who presented with mild microcythemia. 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.
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.
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 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.
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.
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.
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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. [PubMed: 2483933] [Full Text: https://doi.org/10.3109/03630268908998852]
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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. [PubMed: 8718701] [Full Text: https://doi.org/10.3109/03630269509005834]
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. [PubMed: 1703139] [Full Text: https://doi.org/10.3109/03630269009046964]
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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. [PubMed: 6814491] [Full Text: https://doi.org/10.1016/0167-4838(82)90353-3]
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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. [PubMed: 2442122] [Full Text: https://doi.org/10.3109/03630268709005796]
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