title: The triplicated alpha-globin gene locus in beta-thalassaemia heterozygotes: clinical, haematological, biosynthetic and molecular studies.
abstract: Excess alpha-globin chains play a major role in the pathophysiology of homozygous beta-thalassaemia. In beta-thalassaemia carriers a minor effect of alpha-globin chain excess is reflected in a minimal or mild anaemia without clinical symptoms. Factors that increase alpha-chain excess in heterozygotes are expected to accentuate the severity of the clinical and haematological phenotype. We report the clinical, haematological, biosynthetic and molecular data in three beta-thalassaemia heterozygotes with the rare interaction of homozygosity for alpha-globin gene triplication, and in 17 heterozygotes with a single additional alpha-globin gene. The three patients homozygous for the alpha-globin gene locus (anti 3.7 kb arrangement) had beta(0)-thalassaemia mutations and a diagnosis of thalassaemia intermedia, preserving haemoglobin levels around 7-8 g/dl. Of the 17 beta-thalassaemia heterozygotes (six children and 11 adults), 16 had severe beta-thalassaemia mutations interacting with an additional alpha-globin gene (13 with alpha alpha alpha anti-3.7 and four with alpha alpha alpha anti-4.2). Compared to simple beta-thalassaemia heterozygotes, they had lower haemoglobin levels and red cell indices, but higher alpha/beta biosynthesis, HbF levels and reticulocytes. Our results suggest that homozygous alpha-gene triplication interacts with a severe beta-thalassaemia mutation to cause an alpha-chain excess equivalent to that observed in homozygous beta-thalassaemia intermedia. In heterozygotes for severe beta-thalassaemia mutations with one additional alpha-globin gene, the alpha-chain excess causes a more pronounced degree of anaemia than is usually seen in simple beta-thalassaemia heterozygotes.
authors.affiliation: First Department of Paediatrics, Athens University, St Sophia's Children's Hospital, Greece.
authors.forename: J
authors.initials: J
authors.lastname: Traeger-Synodinos
authors.forename: E
authors.initials: E
authors.lastname: Kanavakis
authors.forename: C
authors.initials: C
authors.lastname: Vrettou
authors.forename: E
authors.initials: E
authors.lastname: Maragoudaki
authors.forename: T
authors.initials: T
authors.lastname: Michael
authors.forename: A
authors.initials: A
authors.lastname: Metaxotou-Mavromati
authors.forename: C
authors.initials: C
authors.lastname: Kattamis
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D005914:Globins / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D005810:Multigene Family; D009154:Mutation; D010375:Pedigree; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D005914:Globins