Alternative titles; symbols
HGNC Approved Gene Symbol: HBG1
SNOMEDCT: 191201002; ICD10CM: D56.4;
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:5,248,269-5,249,857 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Fetal hemoglobin quantitative trait locus 1 | 141749 | Autosomal dominant | 3 |
See 142250. Chang et al. (1978) demonstrated that the 5-prime untranslated region of the human gamma-globin mRNA contains 57 nucleotides, compared to 41 in alpha and 54 in beta. Both guanosine and cytidine were found at the 19th nucleotide position from the 5-prime end of the gamma mRNA. This heterogeneity may reflect differences in the A-gamma and G-gamma (142250) loci.
Jeffreys (1979) found a restriction enzyme polymorphism of the DNA intervening sequence of the A-gamma gene. The frequency was estimated at 0.23. Puzzling was the finding of the same polymorphism in the G-gamma gene. See Slightom et al. (1980) and Shen et al. (1981) for a discussion of the possible mechanisms for suppression of allelic polymorphism. Gene conversion is 1 of the 2 classes of known mechanisms that can act on families of genes to maintain their sequence homology; the other is unequal crossing-over (Baltimore, 1981). The similarity of the 2 gamma-globin genes (e.g., identical restriction polymorphism in an intervening sequence) may owe its origin to this mechanism. Slightom et al. (1980) found that IVS-1 is highly conserved and has 122 bases between codons 30 and 31; IVS-2, which consists of conserved, nonconserved and simple sequence DNA and varies in length from 866 to 904 bases, is located between codons 104 and 105. The data of these authors suggested that gene conversion (intergenic exchanges in cis) is a frequent event, occurring in the germline. The gene conversion in the first example found in Smithies' laboratory (Slightom et al., 1980) involved more than a kilobase of DNA. Smithies and Powers (1986) referred to examples of much shorter gene conversions in the human fetal globin gene pair. They suggested that gene conversions are the consequence of a general mechanism whereby DNA strand invasions enable chromosomes to find their homologs during meiosis. The model they suggested had the following elements: In meiosis single-stranded 'feelers' are extruded from many sites along DNA molecules. These feelers can invade any DNA duplex they encounter and then can scan that duplex for homologous sequences with which to form a Watson-Crick double helix. Scanning is halted when a nucleotide sequence is found that can form a stable double helix. If nearby invasions have also been successful, a zipper effect will lead to pairing of homologs. If a stable heteroduplex is formed as a consequence of a related sequence being found at a nonhomologous chromosomal location, short gene conversions may result. Gene conversion is more likely to develop between closely linked genes than between widely separated ones.
Papayannopoulou et al. (1982) demonstrated a humoral factor that induces switching from gamma-globin to beta-globin in neonatal and adult cells. Fetal cells are not responsive to the factor. Weinberg et al. (1983) studied the correlation between gamma-globin and beta-globin synthesis in cultures of erythroid progenitor cells from newborn infants and adults. The findings suggested a clonal model for hemoglobin switching. Lavett (1984) found an extensive stem-loop structure in the A-gamma-globin promoter region, with intron transcripts from epsilon-globin, A-gamma-globin, delta-globin and beta-globin showing sequences complementary to that of the loop. She proposed a model for globin-switching based on changes in DNA secondary structure and intron transcript pairing. Melis et al. (1987) presented evidence that the genes controlling the gamma-to-beta switch are located on human chromosome 11; whether they operate by a cis- or trans-acting mechanism was not resolved by the experiments. Melis et al. (1987) pursued the question of the control of the switch by comparing the chromosomal composition of hybrids between mouse erythroleukemia (MEL) cells and human fetal erythroid cells, producing one or the other kind of human globin, i.e., fetal or adult. Two types of comparison were done. First, the chromosomal composition of primary hybrids expressing human fetal globin was compared to that of primary hybrids that had switched to adult globin production. Second, primary hybrids were subcloned, and chromosomal composition of subclones expressing fetal globin was compared to those switched to adult globin formation. The findings showed that retention of only chromosome 11 is required for expression of fetal globin and for the subsequent shift from fetal to adult globin production. The data showed that the gamma-to-beta switch is controlled by a mechanism that is syntenic with the beta-globin locus. Studies at the level of chromatin have shown that both the fetal and adult globin genes are DNase I hypersensitive in fetal erythroid cells, whereas only the adult globin genes (delta and beta) are DNase I hypersensitive in adult cells (Groudine et al., 1983).
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 promoters of both A-gamma and G-gamma hemoglobins.
Trent et al. (1986) identified a Maori family with 4 copies of a gamma-globin gene on 1 chromosome. A quadrupled gamma gene cluster detected in a Melanesian by other researchers probably had the same origin because it had a similar beta gene haplotype for restriction enzymes. Hemoglobin F levels in adults with quadrupled gamma genes were normal. See 141749 for description of a nondeletion form of hereditary persistence of fetal hemoglobin due to point mutation in the promoter region 5-prime to the A-gamma gene; this form might be called HPFH, nondeletion type A. In the course of analysis of DNA from 852 Island Melanesians, Hill et al. (1986) found a high frequency of single- and triple-gamma-globin genes. All single-gamma genes were A-gamma, all triple-gamma genes were G-G-A, and the 1 instance of a quadruple-gamma gene was G-G-G-A (see Trent et al., 1986). The authors favored intrachromosomal recombination (i.e., between sister chromatids) rather than interchromosomal recombination. In blacks with G-gamma(beta+) HPFH, a C-to-G change is found at position -202.
Carver and Kutlar (1995) identified 27 variants due to mutations in the HBG1 gene, as of January 1995.
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.
Hemoglobin Gamma Regulatory Region
Hematologic correlations with restriction mapping suggest that a region of DNA near the 5-prime end of the delta gene may be involved in the cis-suppression of gamma-globin gene expression in adults (Fritsch et al., 1979). Putative regulation sequences located between the gamma and beta loci, which may have a role in regulating the perinatal gamma-to-beta hemoglobin switch, were also discussed by Jagadeeswaran et al. (1982) and Ottolenghi and Giglioni (1982). Another segment of DNA outside the beta-globin gene cluster (142470) regulates F-cell production in normal persons 'at rest,' under conditions of erythropoietic stress, and in associated thalassemia and hemoglobinopathies. Its separateness is indicated by its loose linkage to the beta globin gene.
The beta-globin locus control region (LCRB; 152424) is a powerful regulatory element required for high-level globin gene expression. Navas et al. (2002) generated transgenic mouse lines carrying a beta-globin locus YAC lacking the locus control region (LCR) to determine if the LCR is required for globin gene activation. Beta-globin gene expression was analyzed by RNase protection, but no detectable levels of epsilon-, gamma-, and beta-globin gene transcripts were produced at any stage of development. Lack of gamma-globin gene expression was also seen in a beta-YAC transgenic mouse carrying the gamma-globin promoter mutant that causes HPFH (142200.0026) and a HS3 core deletion that specifically abolishes gamma-globin gene expression during definitive erythropoiesis. The authors concluded that the presence of the LCR is a minimum requirement for globin gene expression.
Navas et al. (2003) assessed the contribution of the GT6 motif within HS3 of the LCR on downstream globin gene expression by mutating GT6 in a beta-globin locus YAC and measuring the activity of beta-globin genes in GT6-mutated beta-YAC transgenic mice. They found reduced expression of epsilon- and gamma-globin genes during embryonic erythropoiesis. During definitive erythropoiesis, gamma-globin gene expression was significantly reduced while beta-globin gene expression was virtually indistinguishable from that of wildtype controls. Navas et al. (2003) concluded that the GT6 motif is required for normal epsilon- and gamma-globin gene expression during embryonic erythropoiesis and for gamma-globin gene expression during definitive erythropoiesis in the fetal liver.
The human gamma-globin gene and its orthologous gene in the galago (a prosimian primate) evolved from an ancestral epsilon-globin gene (HBE1; 142100). In galago, expression of the gamma gene remained restricted to the embryonic stage of development, whereas in humans, expression of the gamma gene was recruited to the fetal stage. To localize the cis elements responsible for this developmentally distinct regulation, Li et al. (2004) studied the expression patterns of the human gamma gene driven by either the human or the galago gamma promoters in transgenic mice. Gamma gene transcription driven by either promoter reached similar levels in embryonic erythropoiesis. In adult erythropoiesis, the gamma gene was silenced when controlled by the galago gamma promoter, but it was expressed at a high level when it was linked to the human gamma promoter. By a series of gamma promoter truncations, the sequences required for the downregulation of the galago gamma-globin gene were localized to the minimal promoter. Furthermore, by interchanging the TATA, CCAAT, and CACCC elements between the human and galago minimal promoters, Li et al. (2004) found that whereas each box made a developmentally distinct contribution to gamma-globin gene expression, the CACCC box was largely responsible for the downregulation of the gamma gene in adult erythropoiesis. The CACCC box is a common element in the proximal promoters of many housekeeping and lineage-specific genes. All mutations or deletions of this box impair expression of the affected genes, suggesting that the CACCC box functions as a transcriptionally positive element.
Gene therapy for patients with hemoglobin disorders has been hampered by the inability of retrovirus vectors to transfer globin genes and their cis-acting regulatory sequences into hematopoietic stem cells without rearrangement. In addition, the expression from intact globin gene vectors has been variable in red blood cells due to position effects and retrovirus silencing. Sabatino et al. (2000) hypothesized that by substituting the globin gene promoter for the promoter of another gene expressed in red blood cells, they could generate stable retrovirus vectors that would express globin at sufficient levels to treat hemoglobinopathies. They had shown that the human ankyrin (612641) gene promoter directs position-independent, copy number-dependent expression of a linked gamma-globin gene in transgenic mice. They presented further experiments suggesting that constructs between gamma-globin and ankyrin may be valuable for treating a variety of red cell disorders by gene replacement therapy, including severe beta-thalassemia.
In the course of studies of the chemical structure of hemoglobin F in thalassemia, Ricco et al. (1976) found a new fetal hemoglobin in which isoleucine at position 75 was replaced by threonine. It was present in 29 of 32 homozygotes in amounts varying from traces to 40% of all Hb F. It was also found in 40% of normal newborns and premature infants, in a 14-week-old fetus, and in 1 of 3 patients with aplastic anemia and elevated Hb F. The authors concluded that the synthesis of this gamma chain is controlled by a separate locus. The T75 gamma chain was thought to have glycine at position 136. However, Schroeder and Huisman (1979) stated that the T-gamma chain has alanine in position 136. Huisman et al. (1981) further described this polymorphism of the A-gamma chain: A-gamma-I with isoleucine and A-gamma-T with threonine at position 75. From study of many different populations, Huisman et al. (1985) presented data on the frequency of the A-gamma gene that has substitution of threonine for isoleucine at position 75. The frequency varied from zero in 20 Georgia blacks with CC disease to 24% in AA persons in Italy.
See Altay et al. (1988).
See Chen et al. (1985).
See Nakatsuji et al. (1982).
See Nakatsuji et al. (1983).
See Chen et al. (1985).
See Al-Awamy et al. (1985).
See Schneider et al. (1974).
Wrightstone, R.: Augusta, Ga.: personal communication, 1986.
See Hidaka et al. (1989).
See Fuyuno et al. (1981).
See Wada et al. (1983).
See Ahern et al. (1970).
This is named for the street in Ube, Japan, where the family lived (Yoshinaka et al., 1982).
See Lie-Injo et al. (1973).
See Chen et al. (1985).
See Nakatsuji et al. (1982).
See Grifoni et al. (1975) and Saglio et al. (1979). The ile75-to-thr variant is very common and has been found in all ethnic groups, often at a frequency of more than 0.2. In contrast, the ile75-to-thr mutation in the HBG2 gene (142250.0039) is rare (Gu et al., 1995).
The same substitution occurs at the homologous position in the alpha chain in hemoglobin O (Indonesia) and in the beta chain in hemoglobin O (Arab). Glutamine is substituted for glutamic acid at beta 121 in hemoglobin D (Punjab). See Sacker et al. (1967), Care et al. (1983), and Nakatsuji et al. (1985).
See Jenkins et al. (1967).
See Ahern et al. (1975).
See Hu and Ma (1987). Teng and Ma (1991) observed a second example.
See Ma et al. (1987).
See Nakatsuji et al. (1984). Wada et al. (1986) found a frequency of 1 per 2,100 in Japanese neonates.
Huisman et al. (1972) described a new hemoglobin in a healthy Kenyan male. The man was thought to have Hb S in combination with hereditary persistence of fetal hemoglobin. The abnormal hemoglobin was found to have a non-alpha chain with characteristics of the gamma chain at the NH2 end and of the beta chain at the COOH end. The normal Hb F contained only gamma-G chains. From further studies of the family, Kendall et al. (1973) concluded that the order of linked genes is gamma-G, gamma-A, delta, and beta. Crossing-over occurred between residues 81 and 86 of the gamma and beta chains. Among 7 chromosomes carrying the hemoglobin Kenya hybrid gene, Lanclos et al. (1987) found only 1 haplotype. Waye et al. (1992) described a 25-year-old black woman with compound heterozygosity for Hb S/Hb Kenya and a long history of anemia requiring transfusions during childhood and adolescence.
In a Greek HPFH allele, Collins et al. (1985) demonstrated a G-to-A mutation 117 bp 5-prime to the cap site of the HBG1 gene, just upstream of the distal CCAAT sequence. Waber et al. (1985) corroborated the finding that in a particular form of hereditary persistence of fetal hemoglobin in Greeks (141749) a point mutation (G-to-A) 117 nucleotides 5-prime to the cap site of the A-gamma gene is not a neutral polymorphism but rather is causative. In this form of HPFH, A-gamma fetal hemoglobin and beta-globin are synthesized in a 20:80 ratio rather than the normal 0.5:99.5 ratio. Collins et al. (1985) studied the expression of this mutation and of a second promoter mutation, C-to-G, 202 nucleotides 5-prime to the cap site of the G-gamma gene. The latter occurs exclusively in blacks and gives rise to G-gamma-(beta+) HPFH. Waber et al. (1986) presented evidence that the G-to-A substitution at nucleotide 117 5-prime to the A-gamma gene is indeed the cause of the Greek form of A-gamma(beta+) HPFH. In a black family with HPFH, Huang et al. (1987) found a change from G-to-A at position -117 similar to that seen in subjects with Greek A-gamma-HPFH. Haplotype analysis supported the suggestion that the G-to-A substitution occurred as an independent event in this black family. Superti-Furga et al. (1988) found that the -117 mutation in the A-gamma gene in the Greek form of HPFH, which is located immediately upstream of the distal of the 2 CCAAT elements, interferes with the binding of an erythroid cell-specific factor, referred to as NF-E. (NF-E stands for nuclear factor, erythroid.) The findings suggest a possible role of NF-E in the repression of gamma-globin genes in adult erythroid cells.
Ottolenghi et al. (1988) found a frequency of 0.3% for a new form of HPFH in northern Sardinia. They showed that the cloned gene had a substitution of adenine for guanine at position -117 of the A-gamma-globin gene promoter; the same mutation occurs also in Greek HPFH, although associated with different restriction polymorphisms. In Sardinia, another form of HPFH is associated with a -196 C-to-T substitution in the A-gamma-globin gene promoter (Sardinian delta-beta-thalassemia; see 142200.0027). To test directly whether the base substitutions in the promoter regions of the A-gamma-globin gene can result in an increase in A-gamma-globin gene transcription, Rixon and Gelinas (1988) studied cosmid clones containing the entire gamma through beta gene region from persons with Greek-type (G-to-A base substitution at -117) and Chinese-type (C-to-T base substitution at -196) A-gamma-HPFH in a transient expression assay. Consistently, the Greek A-gamma-globin gene produced about 1.4 times as much RNA as the wildtype gene. No difference was documented between the Chinese-type promoter and the wildtype promoter. In the study of Sardinian families with HPFH, Camaschella et al. (1989) found 2 unrelated subjects with unusually elevated levels of fetal hemoglobin (24%), mostly of the A-gamma type. Furthermore, hemoglobin A2 was lower than usual (0.8%). By selective amplification of the HBG1 gene promoter and hybridization to synthetic oligonucleotides, Camaschella et al. (1989) demonstrated that these 2 subjects were homozygous for the -117 mutation. One of them was a 72-year-old woman with 4 healthy children, all heterozygous for HPFH. Berry et al. (1992) found that when the gamma-globin gene containing the G-to-A substitution at nucleotide -117 was introduced into mice, there was persistence of gamma-globin expression at a high level and a concomitant decrease in beta-globin expression in fetal and adult mice. They showed, furthermore, that these changes correlated with the loss of binding of the transcription factor GATA1 to the gamma-globin promoter, suggesting that it may act as a negative regulator of the gamma-globin gene in adults. This stands in contrast to the transactivation properties of GATA1 (Martin and Orkin, 1990; Evans and Felsenfeld, 1991).
In a Chinese person who was heterozygous for a nondeletion form of A-gamma-HPFH (141749), Gelinas et al. (1986) found a cytosine-to-thymine transition at position -196 of the A-gamma gene promoter. This mutation at position -196 has been found in unrelated persons with the same phenotype from Italy and Sardinia. These mutations apparently arose independently since they are associated with different haplotypes. In Italians with the A-gamma (beta+) form of HPFH, Waber et al. (1986) found a C-to-T change at position -196.
In the Sardinian delta-beta-thalassemia, there are 2 mutations: the mutation in the HBG1 gene at position -196 and the beta-0-thalassemia mutation at codon 39 of the HBB gene (141900.0312). The mutation at position -196 is associated with high levels of production of fetal hemoglobin. The beta-39 nonsense mutation may have gotten onto the -196 chromosome through crossing-over. A chromosome carrying such a double mutation could be expected to impart selective advantage because the beta-thalassemia would protect against malaria while the increased gamma-globin production would ameliorate the severity of the beta-thalassemia (Pirastu et al., 1987). This chromosome with mutations in 2 closely linked loci leads to so-called Sardinian nondeletional delta-beta-thalassemia; more frequently, delta-beta-thalassemia results from extensive deletions of the beta-globin gene cluster. Loudianos et al. (1992) sequenced the delta-globin gene (142000) in a case of Sardinian nondeletional delta-beta-thalassemia and found it to be entirely normal. They concluded that the deficient function of the delta-globin gene is probably due to the suppressive effect of the in cis nondeletional high persistence of fetal hemoglobin mutation in the HBG1 gene.
Gelinas et al. (1986) referred to a substitution at position -198 in the A-gamma gene in the British form of HPFH (141749) and to a base substitution at position -202 in G-gamma HPFH. The -200 region may be the site of interaction between the gamma-globin gene and trans-acting elements which turn off the gamma genes in the perinatal period. This interaction may be weakened by the substitutions found in these forms of HPFH.
In a British family with nondeletional type of hereditary persistence of fetal hemoglobin, Tate et al. (1986) identified a -198T-C transition in the 5-prime region of the HBG2 gene. The family had been reported by Weatherall et al. (1975). Homozygotes were clinically and hematologically normal except for increased HbF, ranging from 18 to 21%. Heterozygotes had HbF of 3.5 to 10%. This has been referred to as the British form of HPFH.
See Plaseska et al. (1990).
In a Brazilian female of Caucasian descent with HPFH (141749), Costa et al. (1990) found that one chromosome 11 carried a C-to-G mutation at -195 in the A-gamma promoter. The other chromosome carried a 4-bp deletion (-225 to -222) which was previously described by Gilman et al. (1988). The latter mutation appears to cause a decrease in the level of A-gamma chains. This has been called the Brazilian form of HPFH.
In 2 young black males with hereditary persistence of fetal hemoglobin (141749) who lived in Georgia, Oner et al. (1991) found a C-to-T substitution at position -114 of the HBG1 gene. Their hematologic data were completely normal. Both had levels of Hb F of 3 to 5% above normal; this Hb F contained mainly A-gamma chains. The mutation occurred in the distal CCAAT box (positions -111 to -115). Fucharoen et al. (1990) identified the same mutation, C-to-T, at nucleotide -114 of the HBG2 gene (see 142250.0035.)
In a black newborn baby, Plaseska et al. (1990) found that about 10% of the hemoglobin in a cord blood sample contained abnormal hemoglobin with 2 substitutions, threonine for isoleucine-75 and glycine for alanine-136.
Se Huisman et al. (1991).
A mutation that decreases gamma-globin expression has been described; a 4-bp deletion from -222 to -225 (AGCA) was observed to be associated with reversal of the normal adult 30% G-gamma:70% A-gamma ratio in an American black family with a beta-zero-thalassemia defect on the cis chromosome (Gilman et al., 1988) and also in a patient with triplicated gamma-globin genes and low Hb F (Liu et al., 1988). Harvey et al. (1992) found the same mutation on one allele in affected members of a large Australian kindred with nondeletional A-gamma hereditary persistence of fetal hemoglobin. The other allele was demonstrated to carry the T-to-C mutation responsible for the British type of HPFH (142200.0028). By denaturing gradient gel electrophoresis developed for the identification of point mutations in the 5-prime flanking region of the gamma-globin genes, Gottardi et al. (1992) unexpectedly found the same 4-bp deletion at positions -225 to -222 of the HBG1 gene in several samples and showed that it is a frequent polymorphism; it was present in 15 of 92 alleles examined.
In the course of a newborn screening program for hemoglobinopathies in Macedonia, Plaseska et al. (1994) detected a new HBG1 variant with a his-to-gln substitution at position 2. The infant was healthy. They pointed out that histidine occupies the second position of the beta chain also and that 4 beta-chain variants have a substitution of histidine at position 2. Hb Okayama has the same his-to-gln substitution at beta-2; since it shows decreased 2,3-DPG binding, a similar functional deficit might be expected in Hb F (Macedonia-I). Functional studies could not be performed, however, because of insufficient material.
Patrinos et al. (1998) described a new type of nondeletional hereditary persistence of fetal hemoglobin (141749), due to a C-to-T transition at position -158, relative to the cap site of the HBG1 gene. They identified the mutation in 3 unrelated adult cases presenting slightly elevated levels of fetal hemoglobin (2.9 to 5.1%) and normal hematologic indices. They concluded that the mutation had occurred by 2 independent gene conversion events in the 3 cases studied, and that the mutation in 1 of the 3 cases occurred recently in the parental germline, representing the first example of a de novo gene conversion event identified in humans.
In a blood cord survey for hemoglobinopathies in northern Sardinia, Pirastru et al. (2004) identified a fetal hemoglobin, designated Hb F Porto Torres, having 2 substitutions in the HBG1 gene: ala136 to ser (A136S) and Hb F Sardinia, which is an ile75-to-thr substitution (I75T; 142200.0018). This variant was said to have been the seventh having the sequence of Hb F Sardinia with an additional mutation.
In a study to identify variants responsible for the fetal-to-adult hemoglobin switch involving 1,142 Chinese patients with beta-thalassemia, Chen et al. (2017) identified a G-to-A transition in the +25 position (+25G-A) in the proximal promoter of the HGB1 gene (NC_000011.9:g.5271063C-T, rs368698783), within a highly conserved hexanucleotide LYAR (617684)-binding motif. LYAR is a zinc finger transcription factor that modulates Hb switching by binding the gamma-globin gene and epigenetically silencing HbF. Chen et al. (2017) found that the minor allele (A) of this regulatory SNP impairs LYAR-binding activity and triggers the attenuation of repressive epigenetic regulators DNMT3A (602769) and PRMT5 (604045) from the HBG core promoter, resulting in the demethylation of the promoter CpG sites and the elevation of gamma-globin gene expression in erythroid progenitor cells from beta-thalassemia individuals. Effects of the rs368698783A allele on fetal hemoglobin (HbF) levels (141749) examined from subpopulations from southern China and Thailand showed that the genotypes GA and AA exhibited a significantly elevated level of HbF compared with the GG genotype in each of 3 cohorts from China. The AA genotype exhibited significantly elevated HbF levels compared with GA in thalassemia (cohorts B and C) and HbEE (cohort D) individuals, as well as in 2 unrelated Chinese families with beta-thalassemia intermedia. Moreover, the genotypes AA and GA exhibited a significantly elevated HBG mRNA level compared with the genotype GG in bone marrow-derived CD235a+ erythroblasts derived from the individuals with beta-thalassemia. Hamosh (2021) found that the rs368698783A variant was present in the gnomAD database (v2.1.1) at an allele frequency of 0.193 in the non-Finnish European population and 0.085 in the East Asian population (March 24, 2021).
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Chen, D., Zuo, Y., Zhang, X., Ye, Y., Bao, X., Huang, H., Tepakhan, W., Wang, L., Ju, J., Chen, G., Zheng, M., Liu, D., and 11 others. A genetic variant ameliorates beta-thalassemia severity by epigenetic-mediated elevation of human fetal hemoglobin expression. Am. J. Hum. Genet. 101: 130-138, 2017. [PubMed: 28669403] [Full Text: https://doi.org/10.1016/j.ajhg.2017.05.012]
Chen, S. S., Webber, B. B., Kutlar, A., Wilson, J. B., Huisman, T. H. J. Hb F-Cobb or A-gamma37(C3)trp-to-gly. Hemoglobin 9: 617-619, 1985. [PubMed: 2419280] [Full Text: https://doi.org/10.3109/03630268508997043]
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