Alternative titles; symbols
HGNC Approved Gene Symbol: HBA2
SNOMEDCT: 191187006, 36467003, 68913001; ICD10CM: D56.0, D56.3; ICD9CM: 282.43;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:172,876-173,710 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Erythrocytosis, familial, 7 | 617981 | Autosomal dominant | 3 |
| Heinz body anemia | 140700 | Autosomal dominant | 3 | |
| Hemoglobin H disease, deletional and nondeletional | 613978 | 3 | ||
| Thalassemia, alpha- | 604131 | 3 |
The HBA1 (141800) and HBA2 genes encode identical 141-amino acid proteins (summary by Michelson and Orkin, 1983).
Since at least as early as 1970, 2 alpha loci have been known to exist in some humans (Brimhall et al., 1970): hemoglobins G (Pest) and J (Buda) showed the existence of at least 2 alpha chains in the Hungarians studied (141800.0041, 141850.0008), whereas hemoglobin J (Tongariki) indicated that in Melanesians only 1 alpha locus exists (141800.0077). The alpha locus is apparently double in Chinese (Kan, 1974), whereas in American blacks, chromosomes with single or double alpha loci are about equally frequent (Huisman, 1974). Three members of a Hungarian family had 2 alpha-chain variants (Hb J Buda and Hb G Pest), each variant accounting for 25% of hemoglobin, the rest being Hb A (Brimhall et al., 1974).
Rucknagel and Dublin (1974) estimated that a chromosome with a single alpha locus has a frequency of about 0.27 in American blacks and about 0.36 in African blacks. Rucknagel and Rising (1975) studied an American black family in which of 5 persons heterozygous for hemoglobin G (Philadelphia), an alpha-chain mutant, 3 had about 30% Hb G and 2 had 40%. They suggested that the former persons have 2 alpha hemoglobin loci and the latter persons 1 such locus. From studies of hemoglobin G (Philadelphia), Baine et al. (1976) also concluded that there is variability in the number of alpha-chain genes in the American black population. In heterozygotes the proportion of Hb G (Philadelphia) was trimodally distributed with modes at about 20%, 30%, and 40%. Baine et al. (1976) concluded that gene dosage accounts for this: 1 G gene out of 4 alpha genes leads to 20% Hb G; 1 G gene out of 3 alpha genes leads to 30% Hb G; 1 G gene out of 2 alpha genes or 2 G genes out of 4 alpha genes leads to 40% Hb G.
In Melanesians, Eng et al. (1974) observed homozygous Hb Constant Spring and Hb A.
From study of Hb J (Mexico) in an Algerian family, Trabuchet et al. (1976) also concluded that the alpha gene was duplicate in some chromosomes and single in others.
Although there was no direct proof, Politis-Tsegos et al., 1976 suggested that the 2 alpha-globin genes are closely linked and that unequal crossingover may be responsible for the type of alpha-thalassemia with deleted alpha loci.
Michelson and Orkin (1983) stated that the genes encoding the alpha-like chains of human hemoglobin form a cluster on the short arm of chromosome 16 that spans approximately 30 kb.
Michelson and Orkin (1980) determined that the HBA1 and HBA2 genes differ significantly in the 3-prime untranslated regions.
Straub et al. (2012) reported a model for the regulation of nitric oxide (NO) signaling by demonstrating that hemoglobin alpha, encoded by the HBA1 and HBA2 genes, is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to hemoglobin alpha and is abrogated by its genetic depletion. Mechanistically, endothelial hemoglobin alpha heme iron in the Fe(3+) state permits NO signaling, and this signaling is shut off when hemoglobin alpha is reduced to the Fe(2+) state by endothelial cytochrome b5 reductase 3 (CYB5R3; 613213). Genetic and pharmacologic inhibition of CYB5R3 increased NO bioactivity in small arteries. Straub et al. (2012) concluded that their data revealed a mechanism by which the regulation of the intracellular hemoglobin alpha oxidation state controls nitric oxide synthase (NOS; see 163729) signaling in nonerythroid cells. The authors suggested that this model may be relevant to heme-containing globins in a broad range of NOS-containing somatic cells.
Two types of deletional alpha-plus-thalassemia are identified by molecular genetic studies. One, termed leftward, shows a deletion of 4.2 kb and removes the entire alpha-2 gene; the other, termed rightward, has a deletion of 3.7 kb and gives rise to a hybrid alpha-2/alpha-1 gene. The 3.7-kb rightward deletion can also remove the entire alpha-1 gene and is 'possibly the most common mutation known to produce a genetic disorder' (Bowden et al., 1987). It is prevalent in most tropical and subtropical populations that have been studied, including African and American blacks, Mediterraneans, Southeast Asians, and some Pacific Island populations. In contrast, the 4.2-kb deletion of the alpha-2 gene is very rare in African blacks and Mediterraneans. The leftward one was found only in Asian cases until the report of a case in East Sicily (Troungos et al., 1984).
El-Hazmi (1986) found several persons with the leftward deletion alpha-thalassemia in Saudi Arabia, including homozygotes and heterozygotes. Remarkably, in north coastal Papua New Guinea, the 4.2-kb deletion is found in more than 80% of the population and appears to be going to fixation (Oppenheimer et al., 1984). From comparison of the level of hemoglobin Bart (142309) at birth in homozygotes for each of the 2 deletions, Bowden et al. (1987) demonstrated that the alpha-2 gene, when alone on the chromosome, reduces more alpha-globin than does the alpha-1 gene. (Since hemoglobin Bart is a tetramer of gamma chains, the level of this hemoglobin reflects in an inverse manner the amount of alpha chains produced.)
In a case of alpha-thalassemia, Whitelaw and Proudfoot (1986) showed that the mutation in the 3-prime poly(A) site leads to transcription of the mutant alpha-2 globin gene through into the intergenic sequence past the normal termination site. They interpreted these results as demonstrating that transcriptional termination and 3-prime end processing of mRNA are coupled events for the alpha-2 globin gene.
Liebhaber et al. (1986) studied 8 separate alpha-globin mutants mapped to the alpha-1 or the alpha-2 locus and demonstrated that the alpha-2 gene encodes 2- to 3-fold more protein than the alpha-1 gene. These results suggested that the human alpha-globin cluster contains a major and a minor locus and that deletions in the alpha-2 gene are more significant in the generation of the alpha-thalassemia phenotype than are deletions in the alpha-1 gene.
N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2 is involved have been arbitrarily listed under HBA1 (141800).
In this variant hemoglobin, named for the community in Jamaica where it was first discovered (Clegg et al., 1971), alpha chains have 172 amino acids rather than the normal 141. Clegg et al. (1971) suggested that this may reflect a chain termination mutation. Hb Constant Spring represents 1 to 2% of the hemoglobin of heterozygotes. When combined with an alpha-thalassemia mutation, Hb H disease (613978) results. It is the alpha-2 or 5-prime alpha-globin gene that is mutant in hemoglobin Constant Spring. Hemoglobin Tak (141900.0279) is a termination defect of the beta chain.
Hunt and Dayhoff (1972) searched 518 known protein sequences for a 31-amino acid sequence with the largest number of identities to that of the extra piece on hemoglobin Constant Spring. The sequence that had the greatest identity (9 amino acids) was the region 68-98 of the normal alpha chain. See hemoglobin Wayne (141850.0004) for further discussion.
By use of allele-specific oligonucleotide probes, Kosasih et al. (1988) demonstrated that Hb Constant Spring in a Batak Indonesian family was due to replacement of T by C in the TAA terminal codon of the alpha-2-globin gene, changing it to CAA, the codon for glutamine. This resulted in read-through of the untranslated sequence of the mRNA.
Hsia et al. (1989) described a sensitive and specific DNA-based screening test for improved detection of the Constant Spring variant using polymerase chain reaction (PCR) and allele-specific oligonucleotide slot-blot hybridization. Since the Constant Spring protein is difficult to detect by electrophoresis, Hsia et al. (1989) suspected that the true incidence of the Constant Spring variant may be greater than previously suspected on the basis of protein electrophoresis.
Laig et al. (1990) found Hb CS gene frequencies between 0.05 and 0.06 in northeastern Thailand. The Lao-speaking populations of the Mekong River basin were found to have the highest frequencies of the gene in Southeast Asia.
To identify nondeletion types of Hb H disease in Guangxi, China, Wen et al. (1992) designed 3 primers: one specific for HBA1 DNA, another specific for HBA2 DNA, and a third that was common to the 2. In 27 of 59 Hb H cases (45.8%), it was possible to confirm the disorder as nondeletional in type. Of these, 22 (81.5%) had the Hb Constant Spring mutation and one had the Hb Quong Sze mutation (141850.0005). The nondeletion Hb H disease in Guangxi seemed to be more severe than the deletion types.
Abnormally long alpha chain. Lysine is the 142nd amino acid. Glutamine is the corresponding amino acid in the abnormally long alpha chain of Hb Constant Spring (141850.0001), which like Hb Icaria is the result of a terminator mutation (Clegg et al., 1974). The mutation is a TAA-to-AAA change in codon 142 of the alpha-2 chain, converting it from 'stop' to lysine. In a Yugoslavian teenager with moderate anemia with severe microcytosis and hypochromia and 16% Hb H, Efremov et al. (1990) identified the TAA-to-AAA mutation at codon 142 of the alpha-2 globin gene. The patient also had an alpha-thalassemia-1 deletion of about 20.5 kb, common in Mediterranean populations. The one remaining alpha-1 globin gene was apparently able to compensate sufficiently for the loss of the 3 alpha-globin genes to maintain a hemoglobin level of 8-9 g/dl.
The interaction of Hb Icaria with the Mediterranean type of alpha thalassemia resulted in severe Hb H disease (613978); splenectomy resulted in marked amelioration of clinical features (Kanavakis et al., 1996).
Excessive length of alpha-like chain (with at least 156 amino acids rather than 141). De Jong et al. (1975) found that about 10% of members of the Koya Dora tribe in Andhra Pradesh, India, carry this variant hemoglobin. They found 2 persons with 2 alpha chain variants, Hb Rampa and Hb Koya Dora, plus normal Hb A. This indicates that this population carries 2 alpha chain loci. Hb Koya Dora resembles Hb Constant Spring (141850.0001) in many respects including its alpha-thalassemia-like expression. Serine is substituted at position 142 of the alpha-2 chain (glutamine in Hb Constant Spring and lysine in Hb Icaria).
Two hemoglobins, Hb W1 and Hb W2, with anomalous alpha chains were observed in several members of a family. The alpha T-14 peptide was replaced by a new peptide which was different in the 2. The sequence in Hb A which was missing was thr-ser-lys-tyr-arg-COOH. In W1 it was replaced by thr-ser-asn-thr-val-lys-leu-glu-pro-arg-COOH. Hb W2 had the same peptide except that aspartic acid had been substituted for asparagine in the third position. This was believed to represent the result of enzymatic deamidation of Hb W1. This was the first reported frameshift mutation in man. Deletion of a single nucleotide yields the sequence observed in Hb W1. If the usual nucleotide sequence in the alpha chain gene is ACX.UCX.AAA(G).UAC.CGU.UAA signifying thr-ser-lys-tyr-arg-terminator, then hemoglobin Wayne has had a deletion of the third nucleotide of codon 139 resulting in frameshift to ACX.UCX.AAU.ACC.GUU.AAG.CUG.GAG etc., which reads thr-ser-asn-thr-val-lys-leu-glu-etc. This interpretation agrees with that for hemoglobin Constant Spring (141850.0001), which appears to be a change in the first nucleotide of the terminator codon so that the above sequence becomes ACX.UCX.AAA.UAC.CGU.CAA.GCU.GGA etc., which is read as thr-ser-lys-tyr-arg-gln-ala-gly-etc. The mutation in Hb Wayne is in the alpha-2 gene. See Seid-Akhavan et al. (1976) and Stamatoyannopoulos et al. (1980). In a Canadian family of Scandinavian descent, Salkie et al. (1992) described Hb Wayne in a mother and all of her 4 children.
Goossens et al. (1982) described another nondeletion mechanism: mutation in the 125th codon of the alpha-2 gene resulted in substitution of proline for leucine in a region of the H helix of the alpha-globin chain, which is critical for alpha-beta contact, resulting in impediment to alpha-beta dimer formation, the initial step in hemoglobin tetramer assembly. Thus, the alpha-thalassemia phenotype results from a novel posttranslational mechanism. Goossens et al. (1982) named the mutant Quong Sze, after the province in China where the mother of their proband was born. Liang et al. (1991) reported a second example of this mutation in a Chinese family in Guangxi (Quong Sze). Hb Quong Sze is a highly unstable alpha-chain variant; because the abnormal alpha chains are rapidly catabolized, the abnormal hemoglobin is difficult to detect in reticulocytes. Identification was made through gene analysis.
In the alpha-2 chain of hemoglobin from a Caucasian female with mild hemolytic anemia, Wilson et al. (1989) demonstrated substitution of methionine for valine at position 62. Dot-blot analysis of amplified DNA using synthetic oligonucleotide probes confirmed the suspected G-to-A mutation in the first position of codon 62; GTG was changed to ATG.
See Sanguansermsri et al. (1979). Hb Suan-Dok has an alpha-thalassemia-like effect due to low production and instability of the altered alpha-globin chain. Since the mutation (CTG to CGG) creates a new SmaI restriction site, Hundrieser et al. (1990) diagnosed the mutation by restriction analysis. Furthermore, they confirmed location of the mutation in the HBA2 gene. The hemoglobin was identified in a family from the province of Lampang in Northern Thailand. Weiss et al. (1990) concluded that the thalassemia associated with the Suan-Dok mutation results from instability of the mutant alpha-globin.
Regtuijt et al. (2004) described Hb Suan-Dok in a 58-year-old black female from Curacao (West Indies) with persistent microcytic hypochromic anemia.
Hb J (Buda) and Hb G (Pest) (141800.0041), both alpha-chain mutants, occurred together in a Hungarian male with erythrocytosis (ECYT7; 617981). The occurrence of some normal Hb A in this man showed the existence of at least 2 alpha loci. See Hollan et al. (1972) and Brimhall et al. (1974). By selectively amplifying the alpha-1 and alpha-2-globin cDNAs and hybridizing them to allele-specific oligonucleotides, Mamalaki et al. (1990) demonstrated that the J-Buda variant has a change in the alpha-2 gene, namely, a change from AAG to AAC in codon 61.
See Ahern et al. (1976). Cash et al. (1989) demonstrated that the Spanish Town mutation is located in the HBA2 gene.
See Liddell et al. (1964), Marti et al. (1964), Silvestroni et al. (1967), and Harano et al. (1984). This is a mutation of the HBA2 gene (Cash et al., 1989).
The hemoglobin I mutation is curious in that it is encoded at both the HBA1 locus (see 141800.0055) and at the HBA2 locus (Liebhaber et al., 1984). This is presumably an example of gene conversion.
See Silvestroni et al. (1960, 1960), Bianco et al. (1963), Halbrecht et al. (1967), Ostertag and Smith (1968), Charache et al. (1969), Nagel et al. (1969), Lehmann and Vella (1974), Tentori (1977), and Pich et al. (1978). The family in which hemoglobin Sealy was found was Ashkenazi (Schneider et al., 1968). (Hemoglobin Beilinson was also found in an Ashkenazi Jewish family and has a substitution of glycine for aspartic acid at alpha 47.) See Benesch et al. (1982). This is a mutation of the HBA2 gene (Cash et al., 1989).
See Brimhall et al. (1975), Huisman et al. (1980), and Mrad et al. (1988). The designation of this hemoglobin was changed to Hb Montgomery when it was discovered that Hb Birmingham had already been used for an alpha variant hemoglobin from Birmingham, England (Hb J Birmingham) (Schneider, 1974). This is a mutation of the HBA2 gene (Cash et al., 1989).
See Dherte et al. (1959), Atwater et al. (1960), Raper et al. (1960), Baglioni and Ingram (1961), Gammack et al. (1961), Huehns and Shooter (1961), McCurdy et al. (1961), Minnich et al. (1962), Weatherall et al. (1962), Dance et al. (1964), Chernoff and Pettit (1965), Schroeder and Jones (1965), Sancar et al. (1980), Surrey et al. (1980), Bruzdzinski et al. (1984), and Morle et al. (1984). This is a mutation of the HBA2 gene (Cash et al., 1989).
See Reed et al. (1974). This is a mutation of the HBA2 gene (Cash et al., 1989).
Aguinaga et al. (2000) found the same hemoglobin variant in a nonsmoking 49-year-old Caucasian male who presented with polycythemia (ECYT7; 617981). The authors stated that this was the first report of Hb Inkster associated with polycythemia in a patient with an otherwise unexplained erythrocytosis.
(Polycythemia, erythrocytosis, and erythremia are synonyms meaning increased red blood cell mass. Authors use the terms interchangeably, although erythremia is now almost obsolete.)
In a 22-year-old white man who was undergoing assessment for erythrocytosis (ECYT7; 617981), Perry et al. (1991) found a hemoglobin variant resulting from substitution of valine for alanine-88 in the alpha-2 chain.
Harkness et al. (1990) and Plaseska et al. (1990) identified this variant hemoglobin in an Asiatic Indian child and an Asiatic Indian adult, respectively. The child was apparently homozygous for a G-to-C mutation in codon 130 of the alpha-2-globin gene resulting in marked microcytosis and hypochromia. The patient reported by Plaseska et al. (1990) was heterozygous. The change at codon 130 was GCT-to-CCT.
Ho et al. (1996) found Hb Sun Prairie in an Asian-Indian family in which 2 daughters were homozygous for this unstable alpha-2-globin variant. They showed chronic hemolysis, whereas the heterozygous parents were asymptomatic with a thalassemia carrier phenotype, distinct from the chronic hemolytic state previously described in a heterozygote. Unlike the earlier cases in which family studies were not available, this family clearly exhibited autosomal recessive inheritance, unusual among variants within the same region of helix H. Globin chain biosynthesis ratios initially suggested a beta-thalassemic hemoglobinopathy; this was excluded by normal sequence analysis of both beta-globin genes.
Sarkar et al. (2005) studied the effects of coinheritance of the Hb Sun Prairie mutation with a point mutation in the 5-prime UTR on the same HBA2 chromosome in both heterozygous and homozygous states in the eastern Indian population. Depression of translation because of the second mutation of a conserved base in the 5-prime UTR was thought to account for clinical severity.
See Johnson et al. (1981, 1983). Hb Boyle Heights was originally observed in an adult Mexican male. Zhao et al. (1990) observed it in a Caucasian family living in South Carolina. They demonstrated that the mutation is in the major alpha-globin gene, Hb A(2).
Wilson et al. (1990) found a new, stable alpha-chain variant in 2 members of a Caucasian family living in Iowa. Hematologic data were within normal limits. The hemoglobin moved between Hb A and Hb F in isoelectric focusing (IEF) and eluted slightly faster than Hb A2 in cation exchange HPLC. The family was of German descent. Replacement of asparagine by histidine at position 78 was identified.
Pirastu et al. (1984) demonstrated that a nondeletion form of alpha-thalassemia was due to an initiation codon mutation (AUG to ACG) changing methionine to threonine.
Ayala et al. (1996) studied 10 Spanish families with nondeletional alpha-thalassemia. In 9, they identified a 5-bp deletion at the donor site of IVS1; in 1 case, they identified the ATG-to-ACG transition in the initiation codon.
In an American black woman with alpha-thalassemia, Liebhaber et al. (1987) demonstrated a premature termination mutation at codon 116 (GAG to UAG) changing a glu residue to 'stop.'
In a family ascertained on the basis of hemoglobin H disease (613978), Olivieri et al. (1987) found a new nondeletion form of alpha-thalassemia mutation, an A-to-G substitution in the initiation codon of the HBA2 gene that changed methionine to valine. This mutation abolished an NcoI restriction site and was therefore detectable in genomic DNA by Southern blot analysis.
In a 56-year-old Japanese female who by HPLC appeared to have an abnormally high level of Hb A(1c), Orisaka et al. (1992) found a lys139-to-glu mutation. The mother and 1 of 3 brothers also had the abnormal hemoglobin. The mutation in Hb Tokoname (141800.0149) resides in the same codon. The oxygen affinity properties of the 2 hemoglobins are similar. A second case of Hb Hanamaki was described by Rahbar et al. (1994) in an American family with erythrocytosis (ECYT7; 617981).
In a large family from southern Turkey, Yuregir et al. (1992) observed nondeletional alpha-thalassemia-2 resulting from an A-to-G mutation at nucleotide 4 in the polyadenylation signal of the HBA2 gene: AATAAA to AATGAA. The same A-to-G replacement was present in the alpha-1 pseudogene. The mutation must cause a considerable alpha-chain deficiency as evidenced by the hematologic data in 5 members of a family with Hb H disease (613978) due to compound heterozygosity for alpha-thalassemia-1 and the newly discovered poly(A) mutation.
Giordano et al. (1994) reported a new alpha chain variant (Hb Kurdistan) in a 15-year-old Kurdish refugee girl and her family from Amdea, Iraq. Amplification and DNA analysis of both alpha genes indicated an asp-to-tyr substitution (GAC-to-TAC) at position 47 of the HBA2 gene. Replacement with the larger aromatic side chain of tyrosine at this position does not induce any significant instability in the hemoglobin molecule. In the proband's brother, this variant was associated with a beta-thalassemia nonsense mutation at codon 39.
Hb Agrinio was discovered by Hall et al. (1993) in 3 individuals of Greek origin with an atypical form of Hb H disease (613978) characterized by a severe hypochromic, microcytic anemia. Hall et al. (1993) indicated that the mutation consisted of a T-to-C transition in codon 29 of the HBA2 gene causing a leucine-to-proline transition. Although each affected individual was a compound heterozygote for Hb Agrinio and a previously described mutation affecting the poly(A) addition signal of the HBB gene (141900.0383), simple heterozygotes for the leu29-to-pro mutation have the phenotype of the alpha-thalassemia trait.
Traeger-Synodinos et al. (1998) reported the first case of homozygosity for Hb Agrinio. The leu29-to-pro amino acid substitution in alpha-2-globin was caused by a CTG-to-CCG transition. The 12-month-old Greek proband presented with marked hypochromic microcytic anemia, a very low level of Hb H, rare Hb H inclusions, and a balanced alpha/non-alpha biosynthesis ratio. At the age of 13 years, the proband had a clinical phenotype compatible with mild thalassemia intermedia with moderate anemia (Hb = 7-8 g/dL), normal growth and development, slight splenomegaly, and minimal bone changes, while Hb H and inclusion bodies were not detected.
In a Laotian girl with hemoglobin H disease (613978), Waye et al. (1994) found a TAA-to-TAT mutation converting the termination codon to a tyrosine residue. The mutation gave rise to an elongated mRNA that would code for an alpha-globin chain of 172 amino acid residues instead of the normal 141 residues. The proband's father also carried the mutation. The proband was a compound heterozygote for the Southeast Asian alpha-thalassemia-1 deletion and the novel termination codon mutation. Four previous mutations involving the termination codon of the alpha-2-globin gene had been reported: Hb Constant Spring (141850.0001); Hb Icaria (141850.0002); Hb Koya Dora (141850.0003); and Hb Seal Rock (141850.0028).
Hemoglobin Seal Rock carries a TAA-to-GAA mutation that converts the termination codon of the HBA2 gene to glu (Bradley et al., 1975; Bunn and Forget, 1986). Like 4 other mutations in the termination codon of the HBA2 gene, the mutant allele codes for an alpha-chain variant of 172 amino acid residues that result in unstable elongated mRNA molecules.
So-called 'silent' hemoglobin variants are characterized by the replacement of an amino acid with one having a similar charge. These are usually detected by separations in isoelectric focusing or HPLC because of differences in hydrophobicity. The substitution occasionally may affect the function of physicochemical properties of the variant to determine the clinical or hematologic condition of its carrier. Kazanetz et al. (1995) identified an ala111-to-val substitution in the core peptide of HBA2 due to a change from GCC to GTC. The variant was discovered in a Caucasian baby born in the Anamosa Community Hospital in Anamosa, Iowa, and in his father. Stability tests on all red cell lysates gave negative results, indicating stability of the variant hemoglobin.
In a large Caucasian family, Prchal et al. (1995) found that members with congenital Heinz body hemolytic anemia (140700) were carriers of Hb Bibba. Instability of the variant complicated isolation of the protein from shipped blood samples. The mutation at codon 136 of the alpha-2 gene resulted in a change from CTG to CCG and a leu136-to-pro substitution. The first Hb Bibba heterozygote, characterized in 1968 by Kleihauer et al. (1968), was believed to be a member of this family. The clinical expression of the disease was surprisingly variable in severity. Affected persons in 4 generations of the Alabama family had been observed. (Note that the mutation here is located in the HBA2 gene rather than in the HBA1 gene, as previously indicated in 141800.0011.)
Morle et al. (1995) found homozygosity for a mutation in the HBA2 gene resulting in hemolytic anemia associated with a low level of hemoglobin H. The mutation was a TGC-to-TAC transition involving codon 104 and resulting in replacement of a cysteine by tyrosine. In vitro and in vivo biosynthetic studies suggested that the mechanism leading to Hb H disease (613978) in this homozygous patient was related mostly to a significant instability of the dimers between normal beta chains and variant alpha chains.
Khan et al. (2000) identified Hb Sallanches in a Pakistani family having 3 homozygous patients with transfusion-dependent Hb H disease. The 2 previous reports had been of a French patient and a West Indian patient. The Pakistani cases were thought to have originated as an independent mutation.
Efstratiadis et al. (1980) suggested that slipped strand mispairing (SSM) is enhanced by short (2 to 8) direct repeats, which may induce short deletions in mammalian DNA. SSM was later suggested to play an important in the expansion of trinucleotide repeats, causing neurodegenerative disorders such as spinocerebellar ataxia and Huntington disease. In addition, the size variation of microsatellite repeats, such as polymorphic markers, is also thought to result from SSM. SSM probably also leads to the variability in microsatellite repeats seen in tumor cells, reflecting the high degree of genomic instability in those tissues. Thus, SSM appears to be occur both in germline and in somatic cells. Slippage of the replication fork is not in itself sufficient to explain the more complex mutations in which small deletions are combined with insertions. Oron-Karni et al. (1997) described a deletion/duplication mutation in the HBA2 gene that allowed them to formulate a novel mechanism accounting for the generation of this mutation, as well as a number of other human mutations. They found a deletion of 9 bp (codons 39 to 41), which was replaced by a nucleotide insertion, duplicating the adjacent downstream sequence. They proposed that the mutation arose by SSM, creating a single-stranded loop, followed by DNA elongation, strand breathing, and the formation of a mismatch bubble. They found in the literature 6 additional deletion/insertion mutations in humans in which the inserted nucleotides came from the same DNA strand. Their model explained all 6 mutations, suggesting that rearrangement of a mismatch loop or bubble during DNA replication may be not uncommon. The patients in whom they made their initial observations were 2 unrelated individuals of Yemenite-Jewish origin, referred for evaluation of unexplained mild microcytic anemia. The hematologic data were compatible with alpha-thalassemia trait. Because of the rarity of the mutation and the fact that it had been found only in the 2 individuals of Yemenite-Jewish origin, The subjects may have had a common ancestor.
See Jogessar et al. (1988). This variant resulted from a TAC (tyr)-to-TAA (stop) transversion in codon 140 of the alpha-globin gene.
Rahbar et al. (1997) described the first example of a trinucleotide deletion in the HBA2 gene. In a Mexican-American family, they found that a slightly unstable alpha-chain hemoglobin variant was due to deletion of an aspartic acid residue through the deletion of GAC at codon 74 or codon 75 of the HBA2 gene.
Cohen-Solal et al. (1998) studied a Guinean woman who was heterozygous for hemoglobin S and had episodes of marked anemia, repeated typical metaphyseal painful crises, and hemosiderosis. Her sickling syndrome resulted from the association of Hb S trait with a severe pyruvate kinase (PK) deficiency (266200) leading to a 2,3-diphosphoglycerate (DPG) concentration of twice normal. Sequencing of the PKLR gene revealed a previously undescribed mutation within exon 5: a 2670C-A transversion, leading to a ser130-to-tyr amino acid substitution (609712.0010), which the authors referred to as 'PK Conakry.' In addition, the patient carried a new hemoglobin variant, leu80 to val, referred to as 'Hb Conakry,' which seemed to have a mild effect. The high intraerythrocytic 2,3-DPG concentration induced by the PK deficiency resulted in a decreased oxygen affinity which favored sickling to a level almost similar to that of S/C compound heterozygous patients.
See Tangheroni et al. (1968) and Manca and Masala (1989).
Paleari et al. (1999) provided molecular characterization of hemoglobin J (Sardegna), which is particularly widespread in northern Sardinia. They characterized the variant at the DNA level as a change of codon 50 of the HBA2 gene from CAC to AAC, predicting a his-to-asn substitution. Protein analysis, however, showed a his-to-asp substitution in the same position. A possible explanation for these findings is that a C-to-A mutation caused the substitution of his for asn, and that the new asn residue subsequently underwent a posttranslational partial deamidation to asp. Indeed, Paleari et al. (1999) identified both the asp and the asn forms of Hb J (Sardegna).
In addition to J (Sardegna), 6 other rare Hb variants had been reported in which deamidation of an asn residue to an asp occurred as a spontaneous posttranslational modification: Hb J (Singapore) (141800.0075), Hb La Roche-sur-Yon (141900.0482), Hb Osler (141900.0211), Hb Providence (141900.0227), Hb Redondo (141900.0404), and Hb Wayne (141850.0004).
Perea et al. (1999) provided the molecular characterization of a hemoglobin variant in a Mexican family. Located in the HBA2 gene, an asp126-to-asn amino acid substitution resulted in a variant with high oxygen affinity. Previously described in 4 families with Mexican ancestors, the variant was known as Hb Tarrant (Moo-Penn et al., 1977).
During a systematic hematologic study, Kister et al. (1999) identified a val1-to-gly mutation in the HBA2 gene in a 24-year-old woman who came from Madagascar. The mutation is a clinically silent variant in which the structural modification disturbs the oxygen-linked chloride binding.
This variant was numbered based on the first amino acid of the mature protein. In the gene-based system of counting, this variant is VAL2GLY.
Lacan et al. (1999) found Hb Boghe in a 12-month-old girl who was treated for malignant histiocytosis at 9 months of age and received a bone marrow transplant from her sister. Hb Boghe was undetectable by isoelectrofocusing and high performance liquid chromatography of hemoglobins. It was only revealed by polyacrylamide gel electrophoresis of globin chains in the presence of urea-Triton X-100 and accounted for 10% of the total hemoglobin. The amino acid change resulted from a CAC-to-CAA mutation in codon 58.
In 2 apparently unrelated diabetic women living in different parts of France, Badens et al. (1999) found a hemoglobin variant during chromatographic measurement of glycated Hb. Codon 77 of the HBA2 gene was found to be changed from CCC (pro) to CAC (his).
Waye et al. (2000) reported a second instance of Hb Toulon in a Canadian family of Italian descent.
Caruso et al. (2002) described what they referred to as the first Italian case of Hb Toulon.
Wenning et al. (2000) identified an electrophoretically silent hemoglobin variant in a healthy 9-year-old Caucasian Brazilian boy and his mother. The variant, which the authors called Hb Campinas, was a single base substitution at codon 26 of the alpha-2 globin gene: GCG (ala) to GTG (val).
Prehu et al. (2000) identified Hb Nikaia, a CAC-to-GAC change in the HBA2 gene resulting in a his20-to-asp substitution, in a 50-year-old French Caucasian man during measurement of glycated hemoglobin. The name of the variant was derived from the ancient Greek name of the city of Nice.
In a newborn in Madrid, Spain, Villegas et al. (2000) found an A-to-G transition in exon 2 of the HBA2 gene, changing codon 90 from AAG (lys) to AGG (arg).
In an Argentinian patient with Hb H disease (613978) and her daughter, Noguera et al. (2001) found a splice acceptor consensus point mutation changing AG to AA in intron 2. Their patient was of Arab and Italian ancestry. The phenotypic expression observed in the heterozygote, namely microcytic erythrocytes, slightly hypochromic, was rather more severe than in individuals with a deleted gene. This observation was thought to be in accord with the fact that the mutation affects HBA2, whose level of expression is 3 times higher than that of the HBA1 gene.
McBride et al. (2001) reported a mutation in monozygotic twins and designated it Hb Dartmouth, after the medical center at which the patients were cared for. The mother, of Khmer ancestry, was heterozygous for alpha-thalassemia-1 due to deletion of both HBA1 and HBA2, common in Southeast Asians. The father, of Scottish-Irish ancestry, was a silent carrier of a leu66-to-pro mutation of the HBA2 gene. The twins had severe neonatal anemia requiring transfusion and were compound heterozygotes for the 2 mutations.
In studies of a 6-year-old boy with mild microcytic anemia, Lacan et al. (2001) found a neutral alpha-chain variant involving the HBA2 gene and designated it Hb Gerland. A GTT-to-GCT mutation of codon 55 was predicted to result in a substitution of alanine for valine.
Hb Manitoba (ser102 to arg) was discovered in a Canadian family by Crookston et al. (1970) and was subsequently found in an Italian patient by Sciarratta et al. (1984). Chang et al. (2001) observed the same variant for the first time in an Asian family in Taiwan.
In an apparently well, 6-month-old Caucasian child, Hoyer et al. (2002) found an AAC-to-AAG transversion in codon 9 of the HBA2 gene resulting in an asn9-to-lys (N9K) change. Hb Delfzicht (141800.0208) has the same mutation in the HBA1 gene.
In a 7-month-old Caucasian child who was apparently well and hematologically normal, Hoyer et al. (2002) found a his72-to-asp mutation in the alpha-2 chain. Three other alpha-chain variants had been reported at this site with no apparent abnormality: Hb Gouda (141800.0198), Hb Fuchu-I (141800.0196), and Hb Daneshgah-Tehran (141800.0026). Hoyer et al. (2002) stated that 4 previously reported beta chain variants with substitution of his77 in the beta-globin chain likewise appeared to be without hematologic effect.
In a 34-year-old male of Italian (Calabrian) ancestry who was clinically well and without hematologic abnormality, Hoyer et al. (2002) described a CAC-to-TAC transition in codon 103 of the HBA2 gene, resulting in a his103-to-tyr substitution. The same mutation had been reported in the HBA1 gene as Hb Charolles (141800.0203) in a person of Sardinian origin, who also had microcytosis that may have been due to mutation of the 3-prime polyadenylation site of the HBA2 gene.
In a 1-year-old Caucasian male who was asymptomatic and hematologically normal, Hoyer et al. (2002) found a CTC-to-CGC transversion in codon 113 of the HBA2 gene resulting in a leu113-to-arg (L113R) change.
Hb Rampa, a pro95-to-ser (P95S) change in the HBA2 gene, was first described in a few members of the Koya Dora tribe of Andhra Pradesh, India (De Jong et al., 1971). Additional cases were reported in a person of north European origin (Smith et al., 1972) and a French-Canadian family (Huisman et al., 1978). Hoyer et al. (2002) described Hb Rampa in a 53-year-old asymptomatic male of German ancestry living in the United States.
Brennan et al. (2002) described Hb Manawatu, a pro37-to-leu (P37L) variant of the HBA2 gene, in a 28-year-old female of British descent living in New Zealand who was heterozygous for a CCC-to-CTC transition. The authors stated that the only other recorded mutation at position alpha-37(C2) was Hb Bourmedes, a pro37-to-arg (P37R; 141800.0012) change in the HBA1 gene.
See Schneider and Jim (1961), Lehmann (1962), Swenson et al. (1962), and Lie-Injo et al. (1979). The original Hb G (Chinese) variant was thought to have a beta-chain substitution (Gammack et al., 1961).
Chang et al. (2002) observed this variant in a Taiwanese family and found that it was caused by a G-to-C substitution at the first base of codon 30 (GAG-to-CAG) of the HBA2 gene, resulting in the substitution of a glutamic acid residue by glutamine (E30Q). The mutation created a PstI restriction site and abolished an authentic BstNI site.
Shih et al. (2003) identified Hb G (Chinese) with alpha-thalassemia-1 of the Thai type in a Taiwanese family.
Marinucci et al. (1979) described this hemoglobin variant in a family of Sicilian origin living in Prato (near Florence in northern Italy). De Marco et al. (1992) found Hb Prato in a Calabrian family. The replacement of the arginine residue by serine occurs at position 31 (arg31 to ser; R31S) of the alpha-2-globin chain. Shih et al. (2003) observed this variant in a Taiwanese individual who was a compound heterozygote for Hb Prato and alpha-thalassemia.
Harteveld et al. (1996) described an IVS1-116A-G acceptor splice site mutation in the HBA2 gene, causing a very mild alpha(+)-thalassemia phenotype, in 2 Dutch families.
Harteveld et al. (2003) reported a third independent case of this alpha-thalassemia point mutation in a healthy 23-year-old Dutch woman; this was the first case defining the phenotype in combination with a frequent alpha(+)-thalassemia deletion defect.
Barbour et al. (2000) reported an individual (called ZF) with alpha-thalassemia due to a unique deletion (called alpha(-)-ZF) that removed the HBA1 gene (141800) and the HBQ1 gene (142240) and juxtaposed a region that normally lies approximately 18 kb downstream of the alpha-globin cluster to a site next to the structurally normal HBA2 gene. The alpha(-)-ZF deletion did not remove any positive cis-acting sequences, but expression of the structurally intact alpha-globin gene was stably silenced and, during development, its CpG island became densely methylated and insensitive to endonucleases over a region of approximately 2 kb. Tufarelli et al. (2003) showed that the deletion had truncated the widely expressed gene LUC7L (607782), which is transcribed from the opposite DNA strand. They showed that in the affected individual, in a transgenic model, and in differentiating embryonic stem cells, transcription of antisense RNA mediated silencing and methylation of the associated CpG island. This was identified as a novel mechanism underlying human genetic disease.
In a review of epimutation mechanisms in metabolic disorders including ZF-type alpha-thalassemia, Gueant et al. (2022) discussed that, in a mouse stem cell model, promotor methylation was triggered by antisense LUC7L transcription, which occurred during cell differentiation (as opposed to the epimutation being present in germ cells). Thus, the epimutation was not considered to be constitutional.
Prehu et al. (2003) found a new phe33-to-ser (F33S) variant (designated Hb Chartres) in the HBA2 gene in a 31-year-old female of French origin presenting with mild microcytic hypochromic anemia. No family studies could be performed.
Harano et al. (2003) found a lys139-to-asn (K139N) missense mutation, resulting from an AAA-to-AAC transversion, in a 52-year-old Japanese male. The change was in the same position 139 of the alpha-2 chain as hemoglobin Tokoname (K139T; 141800.0149) and Hb Hanamaki (K139E; 141850.0023), 2 variants found in Japanese, both of which show high oxygen affinity. Harano et al. (2003) found that the nucleotide sequence of Hb Tokoname was ACA instead of AAA at codon 139 of the alpha-2-globin gene. In the case of Hb Hanamaki, 9 of 12 Japanese families found Honshu, the main island of Japan, were investigated, and the nucleotide sequence GAA instead of AAA was identified at codon 139 of the alpha-1-globin gene. However, in 1 family found in Kyushu, the western most main island, the mutation was identified in the alpha-2-globin gene. Thus, 3 different types of mutation at the same codon of the alpha-globin gene were discovered in the same population and, moreover, in the case of Hb Hanamaki, the nucleotide mutation was observed in both the alpha-1- and the alpha-2-globin genes.
In a 58-year-old man of French Caucasian origin living in Lyon, France, Lacan et al. (2004) identified an ala65-to-thr (A65T) mutation in the HBA2 gene. The patient suffered from type II diabetes (125853) and had hepatomegaly, splenomegaly, microlithiasis, hypercholesterolemia, and hypertriglyceridemia.
In a 34-year-old man of French Caucasian origin living in the city of Decines-Charpieu in the south of France, Lacan et al. (2004) identified an ala69-to-thr (A69T) mutation in the HBA2 gene.
Two different research teams, Wajcman et al. (1993) and Owen and Hendy (1994), independently reported this hemoglobin variant, a ser133-to-arg (S133R) substitution. Wajcman et al. (1993) discovered the mutation (named Hb Val de Marne) in 2 French newborns who were first cousins. Owen and Hendy (1994) found the hemoglobin variant (named Hb Footscray) in a 27-year-old male of Polish-Hungarian descent. Position 133 is an internal residue located near the heme pocket and the C-terminal end of the alpha subunit. The mutation from serine to arginine at this position may facilitate the access of oxygen, or water, to the heme iron. When compared to adult hemoglobin (Hb A), the variant hemoglobin's oxygen affinity is increased 1.7-fold and the autooxidation rate is slightly increased.
Ma et al. (2004) demonstrated that the S133R mutation, caused by an AGC-to-AGA transversion, is due to mutation in the HBA2 gene and not in the HBA1 gene. They found the variant in a 15-year-old Chinese girl and her father.
Siala et al. (2004) described a 3-year-old Tunisian girl who had Hb Bart (gamma-4) at birth, later on presenting with moderate anemia, microcytosis, and hypochromia; she had a normal HBA2 level and no abnormal hemoglobin fraction. After excluding most of the common Mediterranean mutations, sequencing of the HBA2 gene identified a heterozygous change of codon 23 from GAG (glu) to TAG (ter) (glu23 to ter). The E23X mutation was also found in the mother in heterozygous state.
In a 79-year-old woman of Surinamese-Hindustani origin with moderate microcytic hypochromic anemia, Harteveld et al. (2004) identified a silent mutation at codon 22 of the HBA2 gene, GGC (gly) to GGT (gly) (gly22 to gly), resulting in a splice donor site consensus sequence between codons 22 and 23. The abnormally spliced mRNA led to a premature termination between codons 48 and 49. The presence of a downstream intron was thought to induce the intracellular degradation of the affected mRNA, through the pathway of nonsense-mediated decay (NMD), thus explaining the alpha(+)-thalassemia phenotype of the patient. The C-to-T transition was said to be the first reported mutation creating a splice donor site in 1 of the alpha-globin genes.
In a patient presenting with persistent hypochromic microcytosis and erythrocytosis, Dutly et al. (2004) identified a G-to-C transversion in the HBA2 gene, resulting in a gly59-to-arg (G59R) substitution. The defect, designated Hb Zurich Albisrieden, was not detected at the protein level and led to alpha-plus-thalassemia.
In a 3-month-old Turkish boy investigated for anemia with hypochromia and microcytosis, Lacan et al. (2005) identified a TCC-to-CCC transition in codon 81 of the HBA2 gene, resulting in substitution of proline for serine (S81P).
In a Spanish family residing in Plasencia with moderate microcytosis and hypochromia, Martin et al. (2005) identified heterozygosity for a CTG-to-CGG transversion at codon 125 of the HBA2 gene, resulting in a leu125-to-arg substitution.
In the course of assaying glycosylated hemoglobin in a diabetic patient, Harano et al. (1995) found a new alpha-chain variant, which they named Hb Kurosaki after the city where the patient lived. Structural analysis demonstrated substitution of glutamic acid for lysine at position 7. From studies of a 30-year-old Thai male with normal hematologic profile at the steady state, Ngiwsara et al. (2005) found the same hemoglobin variant and demonstrated that the mutation was localized to the HBA2 gene and was caused by heterozygosity for an AAG-to-GAG transition in codon 7.
Viprakasit et al. (2005) stated that in Thailand at least 7,000 new cases of Hb H disease (613978) are expected each year, because nearly 25% of the population is heterozygous for either deletional or nondeletional alpha-thalassemia determinants. The clinical phenotypes of affected individuals with Hb H disease are highly variable, ranging from stillbirths in Hb Bart hydrops fetalis to very mild clinical symptoms. Viprakasit et al. (2005) described a rare initiation codon mutation of the HBA2 gene, a 1-bp deletion of thymine at the second nucleotide of the ATG initiation codon, in compound heterozygous state with alpha-0-thalassemia. Other reported changes in the initiation codon of HBA2 are met1 to thr (141850.0020) and met1 to val (141850.0022).
This mutation was described for the first time by Waye et al. (1997) in an 8-year-old Canadian girl of Vietnamese descent. Pallor had been evident since birth, and hypochromic microcytic anemia was first documented at age 20 months.
During a routine hemoglobin analysis for anemia in a 16-month-old boy who lived in Riyadh, Saudi Arabia, Burnichon et al. (2006) identified heterozygosity for an A-T transversion in exon 2 of the HBA2 gene, resulting in an asp75-to-val (D75V) substitution. The child had no hepatomegaly or splenomegaly. This was the sixth hemoglobin variant described at position 75 of the alpha-globin chain.
Eng et al. (2006) studied a newborn male of Hmong descent who had an elevated level of Hb Bart (more than 25%) indicative of Hb H disease. Deletion-specific PCR demonstrated that he was heterozygous for the Southeast Asian alpha-0-thal deletion. PCR amplification and direct nucleotide sequence analysis of the intact alpha-globin gene cluster revealed a 1-bp deletion of adenine from the translation initiation codon (ATG) of the HBA2 gene.
In a patient with hemoglobin H hydrops fetalis (see 236750), Chan et al. (1997) detected a deletion of codon 30 (deltaGAG, glu) in the hemoglobin alpha-2 gene on one chromosome The other chromosome carried a large deletion that removed both alpha-globin genes and the zeta-globin (142310) gene. The mutant protein was apparently highly unstable since there was no detectable radioactive or protein peak upon in vitro globin chain synthesis. HbH was 2.5%, Hb Bart 31%, HbF 28%, and HbA 38.5%. In a review of the literature, Lorey et al. (2001) noted that this patient died minutes after birth at 39 weeks' gestation, with ascites, hepatomegaly, and placentomegaly present.
In a patient with hemoglobin H hydrops fetalis (see 236750), Chan et al. (1997) detected a gly59-to-asp (G59D) substitution on one allele of the HBA2 gene, resulting from a G-to-A transition. Both alpha-globin genes on the other chromosome were removed by the Southeast Asian deletion (Lorey et al., 2001). Fetal blood sampling at 28 weeks' gestation revealed Hb Bart of 39%, HbF 39%, and HbA 9%. An intrauterine transfusion was given at 29 weeks, and the patient was delivered by cesarean section at 34 weeks. The baby survived a turbulent neonatal period and was discharged at 3 months of age. He required monthly transfusions and at age 2 years had passed normal developmental milestones. Chan et al. (1997) noted that this same mutation had been reported in the HBA1 gene (Hb Adana; 141800.0174) and had been coinherited with an alpha-thalassemia-1 deletion on the other allele, resulting in hemoglobin H disease. Chan et al. (1997) suggested that the more severe phenotype in their patient had resulted from the missense mutation's occurrence in the HBA2 gene, which transcribes up to twice as much mRNA as the HBA1 gene.
In a patient of Filipino ancestry with hemoglobin H hydrops fetalis syndrome (see 236750), Lorey et al. (2001) detected a ser35-to-pro (S35P) substitution in the paternal allele of the HBA2 gene that had resulted from a T-to-C transition. The maternal chromosome carried the Filipino deletion removing the alpha-1 (141800), alpha-2, and zeta-globin (142310) genes. Clinical manifestations at birth by cesarean section at 34 weeks included pericardial effusion, fetal distress, jaundice, hepatosplenomegaly, ambiguous genitalia with fourth-degree hypospadias, and bilateral inguinal testes. He required 6 transfusions in the first 4 months of life; thereafter, hemoglobin levels stabilized. At 13 months of age developmental milestones were consistent with an estimated chronologic age of 10 months.
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Lendaro et al. (1992) showed that Hb Dallas has increased oxygen affinity, diminished cooperativity, and reduced Bohr effect.
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