Spectrum of β-thalassemia mutations and their association with allelic sequence polymorphisms at the β-globin gene cluster in an Eastern Indian population

Abstract

In this report, the spectrum of β-thalassemia mutations and genotype-to-phenotype correlations were defined in large number of patients (β-thalassemia carriers and major) with varying disease severity in an Eastern Indian population mainly from the state of West Bengal. The five most common β-thalassemia mutations were detected, which included IVS1-5 (G→C), codon 15 (G→A), codon 26 (G→A), codon 30 (G→C), and codon 41/42 (-TCTT). These accounted for 85% In 80 β-thalassemic alleles deciphered from 56 patients, Including β-thalassemia major and carriers, and 15% of alleles remained uncharacterized In these patients. Expression of the human β-globin gene is regulated by an array of cis-acting DNA elements, including five DNase I hypersensitive sites (HSs) In the locus control region (LCR), promoters that incorporate certain silencer elements, and enhancers at 3′ of the β-globin gene. For detailed studies and to understand the molecular basis of β-thalassemia, we studied two groups of subjects: a group of 12 patients from four families having β-thalassemia major and carrier phenotype and a control group of 26 healthy individuals. In these two groups, we examined portions of the β-globin gene locus control region HSs 1, 2, 3, and 4, which included the (CA)x(TA)y repeat motif, the (AT)xNy(AT)z repeat motif, the Inverted repeat sequence TGGGGACCCCA, the promoter region of the Gγ-globin gene, an (AT)x(T)y repeat 5′ of the silencer region, and the β-globin gene and its 3′ flanking region. We investigated the allelic sequence polymorphisms in these regions and their association with the β-thalassemia mutations to know the possible genotype-phenotype relationship in β-thalassemia patients. An analysis of cisacting regulatory regions showed varied sequence haplotypes associated with some frequent β-thalassemia mutations in this Eastern Indian population. © Wiley-Liss, Inc.