Hemoglobin--Alpha Locus 2

Alternative Names

  • HBA2
  • 5-Prime Alpha-Globin Gene
  • Alpha-Globin Locus, Second
  • Major Alpha-Globin Locus
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OMIM Number





835 bases

No. of Exons


Protein Name

Hemoglobin Alpha Locus 2

Molecular Mass

15258 Da

Amino Acid Count


Genomic Location


Gene Map Locus


Thalassemia is an inherited disease of faulty synthesis of hemoglobin. The name is derived from the Greek word "thalassa" meaning "the sea" because the condition was first described in populations living near the Mediterranean Sea.

Alpha-thalassemias are characterized by decreased hemoglobin alpha chain synthesis; alpha-zero-thalassemia being the condition where no normal alpha globin is produced, and alpha-plus-thalassemia being the condition where there is reduced globin production. There are two alpha globin genes per haploid genome, and alpha thalassemia abnormalities can result from one to four gene deletions. A single alpha gene mutation leads to the silent carrier state (alpha-plus). The two gene mutation is a minor clinical condition, with mild hypochromic, microcytic anemia.

Mutation of three of the alpha genes leads to Hemoglobin H disease, characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. Mutation of all four alpha genes results in Hb Bart hydrops fetalis (Hb Bart) syndrome, typified by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia. Death usually occurs in the neonatal period. No effective treatment is available for Hb Bart syndrome. Occasional RBCs transfusion may be required for patients with HbH disease.

Molecular Genetics

The alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes 4 functional genes and 3 pseudogenes. Hemoglobin alpha is produced throughout fetal and adult life. Two alpha chains combine with two beta chains to constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin.

HBA2 is the gene encoding alpha 2-globin. The alpha 2 and alpha 1 coding sequences are identical. However, the 2 genes differ slightly over the 5-prime untranslated regions and the introns, but significantly over the 3-prime untranslated regions. The HBA2 gene has a dominant expression role; producing 2.6 fold more protein than HBA1. Therefore, mutations in HBA2 usually have more impact than those in HBA1. About 90% of the mutations in these genes are deletions. The 10% point mutations however, are more severe, since they usually affect the HBA2 gene.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinical SignificanceCondition(s)HGVS ExpressionsdbSNPClinvar
3.7 kb delBahrain; United Arab E...chr16:173301-177104PathogenicAlpha-Thalassemia; Hemoglobin H DiseaseNG_000006.1:g.34164_37967del38636
4.2 kb delUnited Arab EmiratesPathogenicAlpha-Thalassemia375752
Constant Spring NM_000517.6:c.427T>CUnited Arab Emirateschr16:173598PathogenicAlpha-Thalassemia; Hemoglobin H DiseaseNG_059271.1:g.5752T>C; NM_000517.6:c.427T>C; NP_000508.1:p.Ter143Gln4146495115624
G (Philadelphia) NM_000517.6:c.207C>RAlgeriachr16:173236Uncertain SignificanceAlpha-ThalassemiaNG_059271.1:g.5390C>R; NM_000517.6:c.207C>R; NP_000508.1:p.Asn69Lys11103360115638
Kurdistan NM_000517.6:c.142G>TIraqchr16:173171Likely Pathogenic,Uncertain SignificanceNG_059271.1:g.5325G>T; NM_000517.6:c.142G>T; NP_000508.1:p.Asp48Tyr28186483415648
Montgomery NM_000517.6:c.146T>GTunisiachr16:173175Uncertain SignificanceNG_059271.1:g.5329T>G; NM_000517.6:c.146T>G; NP_000508.1:p.Leu49Arg4139214615637
NM_000517.6:c.*92A>GUnited Arab Emirateschr16:173692PathogenicAlpha-ThalassemiaNG_059271.1:g.5846A>G; NM_000517.6:c.*92A>G6375006715647
NM_000517.6:c.*94A>GUnited Arab Emirateschr16:173694PathogenicAlpha-Thalassemia; Hemoglobin H DiseaseNG_059271.1:g.5848A>G; NM_000517.6:c.*94A>G63751269375749
NM_000517.6:c.118_124delinsTACTTCYemenchr16:173147-173153PathogenicAlpha-ThalassemiaNG_059271.1:g.5301_5307delinsTACTTC; NM_000517.6:c.118_124delinsTACTTC; NP_000508.1:p.Thr40fs58777682615657
NM_000517.6:c.70G>TTunisiachr16:172982Likely Pathogenic,PathogenicAlpha-ThalassemiaNG_059271.1:g.5136G>T; NM_000517.6:c.70G>T; NP_000508.1:p.Glu24Ter28186481915686
NM_000517.6:c.95+2_95+6delKuwait; United Arab Em...chr16:173009-173013PathogenicAlpha-Thalassemia; Hemoglobin H DiseaseNG_059271.1:g.5163_5167del; NM_000517.6:c.95+2_95+6del41474145375746
Nouakchott NM_000517.6:c.344C>TAlgeria; Mauritaniachr16:173515Likely Benign,Uncertain SignificanceNG_059271.1:g.5669C>T; NM_000517.6:c.344C>T; NP_000508.1:p.Pro115Leu267607269439115

Other Reports


Jassim et al. (1999) described a simple and robust technique to rapidly detect the hemoglobin alpha (T-Saudi) allele. A total of 32 individuals with proven Hb H disease were studied using a novel mismatched-primer PCR-RFLP approach. This technique involves performing PCR with one of the primers having a deliberately introduced mismatch. The mismatch introduces a StuI restriction enzyme site into the product, which can be cleaved using the restriction enzyme. Hb H levels in the analyzed patients ranged between 5-25% due to homozygosity for the alpha (T-Saudi) allele and compound and simple heterozygosity for various alpha thalassemia alleles. Jassim et al. (1999) indicated that compound heterozygotes for -alpha (3.7) and alpha (T-Saudi) mutations will provide a false homozygous pattern for alpha (T-Saudi) mutations.

Two years later, Jassim et al. (2001) utilized PCR amplification, PCR-RFLP, and differential PCR amplification to study the alpha-globin gene in 56 unrelated alpha-thalassemia individuals (age ranging from 14 days to 78 years). With the exception of two, all the other patients were found to have low MCV, MCH, and HbA2. The two exceptional cases were found to have concurrent beta-thalassemia or sickle cell trait. A total of five different alleles were found in the patient population. Of these, the alpha T-Saudi alpha allele was found to be the most common (53%), followed by the deletional -alpha (3.7 kb) allele (32%). The authors conceded that the high frequency of the Saudi allele could be due to a recruitment bias. Other alleles detected were alpha Hph alpha (12%), alpha T-Turkish alpha (1%) and -alpha (4.2 kb) allele (2%). Ten different genotype combinations were found in the study. Of these, homozygosity for the Saudi allele was responsible for all but three cases of HbH. Of the exceptions, one was heterozygous for the Saudi and the Turkish allele. Since both these alleles are poly A signal mutations, the severe phenotype is understandable. The second case was compound heterozygous for -alpha 3.7 and the Saudi allele, whereas the third exceptional case was homozygous for the -alpha 3.7 allele. Jassim et al. (2001) postulated that in both these cases, the -alpha 3.7 allele may be harboring an additional thalassemia mutation. [Jassim N, Al-Arrayed S, Gerard N, Al-Mukharraq H, Al-Ajami A, Ducrocoq R, Nagel RL, Krishnamoorthy R. Molecular basis of alpha-thalassemia in Bahrain. Bahrain Med Bull 2001; 23(1):3-7.]


Adekile et al. (1994) characterized the alpha thalassemia determinants among Kuwaiti Arabs. PCR, hybridization and DNA sequencing techniques were used to analyze 64 alpha-thalassemia chromosomes. Three mutations were identified in 30 chromosomes from patients with HbH disease. These were: Poly A signal mutation in alpha 2-globin gene (86.7%), -alpha (3.7 Kb deletion; 10%), and alpha-5nt alpha (3.3%).


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