Aγ‐haplotypes: A new group of genetic markers for thalassemic mutations inside the 5′ regulatory region of the human Aγ‐globin gene

This study illustrates the relationship between a group of nucleotide variations within the 5′ regulatory region of the Aγ-globin gene [Aγ-588 A→G, Aγ-499 T→A and the 4-bp deletion (Aγ-225 to -222 AGCA)] and the spectrum of δ- and β-thalassemia mutations in the Hellenic population. These sequence variations, screened by means of denaturing gradient gel electrophoresis, form four separate frameworks (Aγ-haplotypes), each one of which was found to be linked in cis with certain δ- and β-thalassemia mutations found in the Hellenic population. In addition, two novel base substitutions inside the 5′ regulatory region of the Aγ-globin gene (Aγ-521 C→A and Aγ-500 C→T) were identified during this study, which together with Aγ-haplotypes seem to be silent polymorphisms during adult life, as indicated by transient expression assays. Our data show that Aγ-haplotypes represent genetic markers for the spectrum of thalassemic mutations, found in the Hellenic population and can constitute an important genetic repository upon which mutations leading to thalassemia and hemoglobinopathies occurred. Am. J. Hematol 66:99–104, 2001. © 2001 Wiley-Liss, Inc.