In vivo expression of the G γ globin gene of foetal haemoglobin

Abstract

Hb F Malta I (cx2GY2117 His-7Arg) is a stable and benign variant of Hb F found in 1.8% of Maltese newborn. It has been considered a valuable marker of the levels of in vivo expression of the human G γ globin gene and the parameters that control differential gene expression. Cord blood samples (n=6780) were analysed by Iso-Electric Focusing (LE.F.) and 1.8% were found to have a Hb F variant with a pI of 7.29 typical of Hb F Malta 1. The mean proportions of G γ Malta I in Hb F, quantified by reverse phase HPLC, were 0.26 ± 0.03 and 0.58 ± 0.06 in Hb F Malta I heterozygotes and homozygotes respectively. Analysis of the β globin gene cluster haplotype in Hb F Malta I homozygotes established that the Hb F Malta I allele occurs on a haplotype Va background (+ + - - - - -++- for the 5'ɛ Hinc IT, 5' G γ Apa I, 5' G γ Xmn I, G γ and A γ Hind III, Ψn and 3'Ψβ Hinc II, 5'β Hinf I, β Ava II and 3'β Barn HI sites respectively). The common Mediterranean haplotypes Va, IIIb, I and IT accounted for 66.2% of the wild-type alleles tested in Hb F Malta I heterozygotes. Another six haplotypes were also commonly found in Hb F Malta I heterozygotes and together accounted for another 20% of wild-type alleles tested. About 13% of wild-type alleles tested in Hb F Malta I hetcrozygotes had haplotypes that appeared only once in the cohort tested. Analysis of the association between polymorphic sites in the β globin gene cluster and G γ globin chain levels, in Hb F Malta I heterozygotes, showed that the 5'ɛ Hinc II, G γ and A γ Hind III, and 3'Ψβ Hinc II sites are linked to significant variations in the proportion of G γ Malta I and G γ globin chains in Rb F. Meanwhile, no particular haplotype in trans to the G γ Malta I allele was found to be associated with high or low G γ globin chain levels in Hb F Malta I heterozygotes. While the Xmn 1 sIte S' to the G γ globin gene was not found to be associated with significant variations in proportion of G γ globin chains in Rb F Malta I heterozygous infants, this site was found to be associated with variations in Hb F and G γ globin chain levels in a population of Maltese β-thalassaemia homozygotes.