title: Genotype-phenotype correlation and report of novel mutations in β-globin gene in thalassemia patients.
abstract: Heterogeneity in thalassemia is due to various modifying factors viz. coinheritance of α-gene defects, abnormal hemoglobin, XmnI polymorphism, variation in repeat sequences present in LCR, and silencer region of the gene. The present work on populations from eastern regions of India was undertaken to study the genetic profile of heterogeneity in thalassemia patients. Mutation analysis in 126 index families revealed the presence of 3 novel mutations: CD2 (-A) in the 1st exon, -42 (C-G), and -223 (T-C) in the promoter region of β-globin gene. The modifying effect of coexisting α-gene defects, and abnormal Hb (HbS) was clearly observed in our study, however ameliorating effect of T allele of XmnI polymorphism was not found. Analysis of the regulatory regions (LCR) exhibited new combinations (CA(15)TA(5) and CA(13)TA(8)) in HS1 region and one (AT)(10)T(3) in (AT)(x)T(y )silencer region. Thus disparate factors, when considered together, were able to explain several of the thalassemic phenotypes, otherwise not explained by the β globin mutations. However, there were still some cases in this group whose molecular origin could not be ascertained. Our findings confirm not only the extensive genotypic and clinical heterogeneity in β thalassemia but also the need to look for more modulators and modifiers to better understand the genotype-phenotype correlation in thalassemia.
authors.affiliation: Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
authors.forename: Rachana
authors.initials: R
authors.lastname: Nagar
authors.affiliation: Varanasi Regional Thalassemia Welfare Society, Varanasi, India.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India. Electronic address: rajiva.raman@yahoo.com.
authors.forename: Rajiva
authors.initials: R
authors.lastname: Raman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D037941:Silencer Elements, Transcriptional; D013789:Thalassemia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D055542:alpha-Globins / Q000235:genetics*; D055544:beta-Globins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C061909:HCLS1 protein, human; D055542:alpha-Globins; D055544:beta-Globins; C028649:endodeoxyribonuclease XmnI; D015252:Deoxyribonucleases, Type II Site-Specific
keywords: AT(x)T(y); Genotype–phenotype correlation; HS1; LCR; Novel mutation; β-Thalassemia