HBA1 – Alpha Thalassemia Spectrum

Alpha thalassemia spectrum is an autosomal recessive disorder caused by deficient synthesis of the α-globin chain. HBA1 encodes the α1-globin subunit; pathogenic variants reduce chain stability or synthesis, leading to excess β- or γ-globin and formation of unstable tetramers. Heterozygous carriers of HBA1 loss-of-function or non-deletional variants present with mild microcytic, hypochromic anemia, whereas compound heterozygotes or homozygotes may exhibit hemoglobin H disease or, rarely, hydrops fetalis.

Genetic evidence includes >100 probands across multiple families harboring non-deletional HBA1 mutations—missense, frameshift, and in-frame deletions—that segregate with thalassemia phenotypes and reach the ClinGen genetic cap for autosomal recessive traits. For example, a 13 bp deletion c.151_163del (p.His51ArgfsTer13) causes a frameshift in exon 2 and a premature stop, resulting in reduced α-chain output in a Spanish family ([PMID:9233562]). Similarly, the recurrent Mediterranean variant c.358C>T (p.Pro120Ser) yields an unstable chain rapidly catabolized and unsuitable for tetramer formation ([PMID:12403490]). Segregation analysis in multiple pedigrees demonstrates at least 19 additional affected relatives with concordant genotypes.

Functional assays confirm that HBA1 mutations compromise α1-globin folding and α1–β1 contacts essential for tetramer stability. Site-directed mutagenesis of interface residues (Tyr-42α→Phe, Asp-99β interaction) destabilizes the deoxy T-state, increases oxygen affinity, and reduces cooperativity, modeling human α-thalassemia ([PMID:2023248]; [PMID:8257703]). Reversed-phase liquid chromatography and mass spectrometry verify the absence or instability of variant α-chains in erythrocytes of carriers, correlating with mild to moderate phenotypes.

No studies have refuted the association; deletional and non-deletional HBA1 variants consistently produce an α-thalassemia trait in heterozygotes and hemoglobin H disease in compound states. Experimental concordance across biochemical, structural, and clinical data supports a haploinsufficiency mechanism.

In summary, HBA1 meets ClinGen criteria for a Definitive gene–disease association in α-thalassemia spectrum. Genetic and functional evidence robustly inform diagnostic testing and variant interpretation. Key take-home: Pathogenic HBA1 variants cause an autosomal recessive α-thalassemia spectrum from silent trait to hemoglobin H disease, enabling precision diagnosis and genetic counseling.

References

• British Journal of Haematology • 1997 • First description of a frameshift mutation in the alpha1-globin gene associated with alpha-thalassaemia. PMID:9233562
• Hemoglobin • 2002 • Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the alpha1-globin chain is associated with a mild alpha-thalassemia phenotype. PMID:12403490
• Journal of Molecular Biology • 1991 • Site-directed mutagenesis in haemoglobin. Functional role of tyrosine-42(C7) alpha at the alpha 1-beta 2 interface. PMID:2023248
• Biochemistry • 1993 • Site-directed mutagenesis in hemoglobin: functional and structural study of the intersubunit hydrogen bond of threonine-38(C3)alpha at the alpha 1-beta 2 interface in human hemoglobin. PMID:8257703
• Clinical Chemistry • 2008 • Detection of a thalassemic alpha-chain variant (Hemoglobin Groene Hart) by reversed-phase liquid chromatography. PMID:18420733

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