title: Identification and molecular characterization of HNF1B gene mutations in Indian diabetic patients with renal abnormalities.
abstract: Heterozygous mutations of the HNF1B gene (HNF1B-MODY or MODY5) are associated with a wide clinical spectrum of renal and extrarenal disease without clear genotype-phenotype correlation. In this study, we investigated the prevalence of HNF1B gene mutations in young Indian diabetic patients with various renal abnormalities. Fifty unrelated young diabetic patients, who also had renal abnormalities, were selected from the electronic records of a large diabetes centre in Chennai, in southern India. All patients were sequenced for HNF1B gene mutations. The whole or partial gene deletion was analyzed by MLPA. Functional characterization of the novel variant (Asn321Asp) was also performed using transcriptional activation and subcellular localization assays. We identified six different HNF1B gene mutations which included four previously reported (-67C>T, Arg165His, IVS2nt+2insT, Met1_Trp557del) and two novel variations (Asn321Asp, IVS3nt-4C>G). The functional study revealed that the novel variation Asn321Asp in both the heterozygous and homozygous state showed similar transcriptional activity, expression levels and normal transportation of protein to the nucleus similar to wild type, suggesting that it is not likely to be pathogenic. This is the first major study of HNF1B-MODY from India and shows that about 10% of young diabetic subjects with renal abnormalities seen at a tertiary diabetes centre harbor HNF1B gene mutations.
authors.affiliation: Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, India.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kanthimathi
authors.forename: Kandasamy
authors.initials: K
authors.lastname: Balamurugan
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Mohan
authors.forename: Coimbatore Subramaniyam
authors.initials: CS
authors.lastname: Shanthirani
authors.forename: Vijay
authors.initials: V
authors.lastname: Gayathri
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Radha
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006367:HeLa Cells; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D011401:Promoter Regions, Genetic; D022821:RNA Splice Sites / Q000235:genetics; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: C496495:HNF1B protein, human; D022821:RNA Splice Sites; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: Asian Indians; MLPA; MODY5; RCAD; South Asians; autoantibody-negative type 1 diabetes; renal cyst