title: The molecular basis of beta thalassaemia in Punjabi and Maharashtran Indians includes a multilocus aetiology involving triplicated alpha-globin loci.
abstract: We have analysed 201 beta-thalassaemia (beta-thal) genes from natives of the Punjab (156) and Maharashtra states of India and found the causative mutation in 200 of them. The most common beta-globin gene mutations differed significantly between these two groups and between these groups and Indian immigrants in the U.S.A. and the U.K. In the Punjabi Indians the IVS-1, nt 1 (G-T) mutation accounted for nearly one-quarter of beta-thal genes, whereas it was 5% or less in the other groups. Likewise, the cap + 1 mutation was much more prevalent in the Punjabis, whereas the nonsense codon 15 allele had a higher frequency in the Maharashtrans of the Bombay region. The common IVS-1, nt5 allele had a frequency of 60% of beta-thal genes in the Maharastrans, 35% in North American immigrants, and only 23% in the Punjabis. Two-thirds of all beta-thal genes in Punjab were found in the merchant caste (Khatri-Arora), whereas the menial caste (Shudra) was highly represented among those with beta-thal genes in Maharashtra. Two novel beta-globin alleles were each found once; a frameshift codon 55 (+A) in Maharashtrans and a frameshift codons 47-48 (+ATCT) in Punjabis. Of three Punjabi patients with beta-thal intermedia in whom only a single severe beta-globin gene mutation was found, two had six alpha-globin genes (homozygosity for a triplicated alpha-globin locus) instead of the normal alpha-globin gene number of four. Thus, these two individuals had a multilocus aetiology of beta-thal and their parents have the unusual recurrence risk of 1 in 8 for conceiving a third with beta-thal intermedia. Since 15% of 126 alpha-globin clusters studies in Punjabis contained either single (10%) or triplicated (5%) alpha-globin genes, the alpha-globin gene number is a frequent modifier of the phenotype of beta-thal in this ethnic group.
authors.affiliation: Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: G
authors.initials: G
authors.lastname: Garewal
authors.forename: C W
authors.initials: CW
authors.lastname: Fearon
authors.forename: T C
authors.initials: TC
authors.lastname: Warren
authors.forename: N
authors.initials: N
authors.lastname: Marwaha
authors.forename: R K
authors.initials: RK
authors.lastname: Marwaha
authors.forename: C
authors.initials: C
authors.lastname: Mahadik
authors.forename: H H
authors.initials: HH
authors.lastname: Kazazian
mesh_terms: D000483:Alleles; D005260:Female; D005914:Globins / Q000235:genetics*; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D005810:Multigene Family; D009154:Mutation; D016133:Polymerase Chain Reaction; D017086:beta-Thalassemia / Q000208:ethnology / Q000235:genetics*
chemical_list: D005914:Globins