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 ␤-thalassemia mutations and genotype-to-phenotype correlations were defined in large number of patients (␤-thalassemia carriers and major) with varying disease severity in an Eastern Indian population mainly from the state of West Bengal. The five most common ␤-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 ␤-thalassemic alleles deciphered from 56 patients, including ␤-thalassemia major and carriers, and 15% of alleles remained uncharacterized in these patients. Expression of the human ␤-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 ␤-globin gene. For detailed studies and to understand the molecular basis of ␤-thalassemia, we studied two groups of subjects: a group of 12 patients from four families having ␤-thalassemia major and carrier phenotype and a control group of 26 healthy individuals. In these two groups, we examined portions of the ␤-globin gene locus control region HSs 1, 2, 3, and 4, which included the (CA) x (TA) y repeat motif, the (AT) x N y (AT) z repeat motif, the inverted repeat sequence TGGGGACCCCA, the promoter region of the G ␥-globin gene, an (AT) x (T) y repeat 5 of the silencer region, and the ␤-globin gene and its 3 flanking region. We investigated the allelic sequence polymorphisms in these regions and their association with the ␤-thalassemia mutations to know the possible genotype-phenotype relationship in ␤-thalassemia patients. An analysis of cisacting regulatory regions showed varied sequence haplotypes associated with some frequent ␤-thalassemia mutations in this Eastern Indian population. Am.

Association of polymorphic pattern of the (AT) × (T)y motif of β-globin gene in North Indian thalassemia patients with variable clinical expression

“…Our results are in concordance of Kukreti, et al (2002) found association with (AT) 8 (T) 5 motif. We also found that 8 (T) 5 motif at a frequency of 28/40 (70%), (AT) 9 (T) 5 4/40 (10%) and (AT) 7 (T) 7 8/40 (20%).…”

“…motif like (AT) 8 (T) 5 , (AT) 7 (T) 7 , (AT) 9 (T) 5 prevalent among thalassemia chromosomes. The (AT) 7 (T) 7 motif seemed only [6]. Bandyopadhyay, et al (2005) [7] reported 65% prevalence of this motif in East India normal population.…”

Effect of Cis Acting Potential Regulators in the Ss Globin Gene Cluster on the Production of HBF in Thalassemia Patients

“…Interestingly, all β thalassemia chromosomes carrying the Codon 15 (G→A) mutation showed the presence of (AT) 9 (T) 5 allele. A study in Eastern Indian population had shown the linkage of known β thalassemia mutations with the (AT) 8 (T) 5 configuration 22. Goncalves et al (1998) reported that presence of both the (AT) 9 (T) 5 sequence configuration at position −530 of the β globin gene and a (C→T) variation at −158 of the G γ globin gene is associated with elevated expression of HbF.…”

Genetic Disorders of the Indian Subcontinent

“…With the advent of polymerase-chain reaction technique [PCR], some of the VNTR loci like D1S80, APOB, and YNZ22 have been analysed and data are now available for population and forensic studies. Some studies have been carried out on the distribution and variation of VNTR loci among the central, western and eastern Indian populations (Papiha et al 1996, Mastana, 1999, Mastana et al 2000, Mastana and Papiha, 2001, Das et al 2002, Das and Mastana, 2003.…”

“…These include Brahmin, Khatri, Dhimer caste groups and Baiga and Gond tribes from Madhya Pradesh, Gadaba, Kuvi-khond, Paroja tribes from Orissa, Thoti and Kolam tribes from Andhra Pradesh. The data from this study (Mastana and Papiha, 2001) combined with other published data on Konkanastha and Maratha from Maharashtra (Das et al 2002) allow calculation of the genetic distances (DA). A UPGMA dendrogram from this analysis [ Figure 3-3] suggests that most of the populations are geographically aligned and correspond to their social/tribal status.…”