THE TRIPLICATED ALPHA-GLOBIN GENE LOCUS IN BETA-THALASSEMIA HETEROZYGOTES - CLINICAL, HEMATOLOGICAL, BIOSYNTHETIC AND MOLECULAR STUDIES

Excess alpha-globin chains play a major role in the pathophysiology of homozygous beta-thalassaemia. In beta-thalassaemia carriers a minor e ffect of alpha-globin chain excess is reflected in a minimal or mild a naemia without clinical symptoms. Factors that increase alpha-chain ex cess in heterozygotes are expected to accentuate the severity of the c linical and haematological phenotype. We report the clinical, haematol ogical, biosynthetic and molecular data in three beta-thalassaemia het erozygotes with the rare interaction of homozygosity for alpha-globin gene triplication,and in 17 heterozygotes with a single additional alp ha-globin gene. The three patients homozygous for the alpha-globin gen e locus (anti 3.7 kb arrangement) had beta degrees-thalassaemia mutati ons and a diagnosis of thalassaemia intermedia, preserving haemoglobin levels around 7-8 g/dl. Of the 17 beta-thalassaemia heterozygotes (si x children and 11 adults), 16 had severe beta-thalassaemia mutations i nteracting with an additional alpha-globin gene (13 with alpha alpha a lpha(anti-3.7) and four with alpha alpha alpha(anti-4.2)). Compared to simple beta-thalassaemia heterozygotes, they had lower haemoglobin le vels and red cell indices, but higher alpha/beta biosynthesis, HbF lev els and reticulocytes. Our results suggest that homozygous alpha-gene triplication interacts with a severe beta-thalassaemia mutation to cau se an alpha-chain excess equivalent to that observed in homozygous bet a-thalassaemia intermedia, In heterozygotes for severe beta-thalassaem ia mutations with one additional alpha-globin gene, the alpha-chain ex cess causes a more pronounced degree of anaemia than is usually seen i n simple beta-thalassaemia heterozygotes.