Developmental effect of the XmnI site on Gγ-globin gene expression among newborn Hb F-Malta-I [Gγ117 (G19) His→ Arg, CAT→ CGT] heterozygotes and adult β+-thalassemia homozygotes

Abstract

Hb F-Malta-I [Gγ117(19)His→Arg, CAT→CGT] is a stable and benign variant of Hb F found in 1.8% of Maltese newborn. We studied 120 Hb F-Malta-I heterozygotes and four Hb F-Malta-I homozygotes. The mean proportion of Gγ-F-Malta-I in Hb F was 0.26 ± 0.03 for the Hb F-Malta-I heterozygotes and 0.58 ± 0.06 for the Hb F-Malta-I homozygotes. The Hb F-Malta-I allele was shown to occur on a background of the common Mediterranean haplotype Va [+ + - - - - - + + -]. Furthermore, the common Mediterranean haplotypes Va, IIIb [- + + + - + + + + -], I [+ + - - - - - + + +] and II [- + - + + - + + + +] accounted for most (66.2%) of the wild-type alleles among the tested Hb F-Malta-I heterozygotes. Different genotypes at the 5′ ε HincII, Gγ and Aγ HindIII, and 3′ψβ HincII sites (but not at the 5′ Gγ XmnI site) were found to be linked to significant variations in the proportion of Gγ-F-Malta-I and Gγ-globins in the Hb F of newborn Hb F-Malta-I heterozygotes. Moreover, the 5′ Gγ XmnI site was found to be associated with variations in Hb F and Gγ-globin levels in a population of adult Maltese β-thalassemia (thal) homozygotes. This implies that a determinant linked to the XmnI site which effects Gγ-globin gene expression is active in anemic adults but not in normal infants.