HbF production in beta thalassaemia heterozygotes for the IVS-II-1 G-->A beta(0)-globin mutation. Implication of the haplotype and the (G)gamma-158 C-->T mutation on the HbF level.

We studied the presence of the XmnI site and the beta-globin haplotype in 24 individuals, carriers of the IVSII-1 G-->A beta(0)-globin mutation, of whom fourteen had no detectable levels of HbF, while ten coming from 5 families, presented HbF levels ranging from 1.7 to 9% of the total Hb. Of these beta-thalassaemia heterozygotes with fetal hemoglobin, 6 were females and 4 were males with median HbF levels of 4.85% and 4% respectively, and an excess of (G)gamma chains (range (G)gamma/(A)gamma: 55/45-70/30). Of the group of carriers of beta-thalassaemia with HbF < 0.1, in all cases except one, IVSII-1 mutation was found associated with XmnI polymorphic site. Haplotype analysis in these individuals revealed that in 10 cases IVSII-1 was linked with haplotype IIIb, in 1 case with haplotype IIIa, and in 3 cases with haplotype IX. On the other hand, in the group of carriers with measurable levels of HbF, IVSII-1 was always associated with haplotype IIIa and the XmnI site was either in-homozygous or the heterozygous state in-cis or in-trans with the mutated beta-globin gene. In conclusion the results of the study of these families seem that XmnI site in-cis with the IVSII-1 does not induce HbF production when this beta(0)-thalassaemia mutation is associated with IIIb or IX haplotype. On the other hand the (G)gamma -158 C-->T mutation is associated with small amounts of HbF in IVSII-1 heterozygotes, when the beta-globin mutation is linked to haplotype IIIa. Copyright 2000 Wiley-Liss, Inc.