Molecular, haematological and clinical studies of the-101 C -> T substitution of the beta-globin gene promoter in 25 beta-thalassaemia intermedia patients and 45 heterozygotes

We report the clinical, haematological, biosynthetic and molecular data of 25 double heterozygote beta-thalassaemia intermedia patients and 45 beta-th alassaemia heterozygotes with the C-->T substitution at nucleotide position -101 from the Cap site, in the distal CACCC box of the beta-globin gene pr omoter. This mutation is considered the most common amongst the silent beta -thalassaemia mutations in Mediterranean populations, Of the 25 compound he terozygotes for the beta -101 C-->T and common severe beta-thalassaemia mut ations, all but one had mild thalassaemia intermedia preserving haemoglobin levels around 9.5 g/dl and haemoglobin F levels <25%. The only transfused patient was characterized to have an additional alpha-globin gene. Strict assessment of haematological and biosynthetic findings in the hetero zygotes for the beta -101 C --> T mutation (excluding six cases with an alp ha-globin gene defect) demonstrated that less than half of them had complet ely normal (silent) haematology; the remainder had either high haemoglobin A(2) values tin the range of 3.7-5.1%) and/or low red cells indices and/or raised haemoglobin F values, The alpha/non-alpha-globin chain synthesis rat ios were generally raised, with mean 1.44 (1.07-2.10). Amongst the parents of the compound heterozygotes, who were not selected for molecular analysis Following haematological screening, half of the cases were completely sile nt. Interaction with severe beta-thalassaemia mutations always resulted in the clinical phenotype of mild non-transfusion-dependent thalassaemia intermedi a.