Identification of Novel Variants in the Hepatocyte Nuclear Factor-1α Gene in South Indian Patients with Maturity Onset Diabetes of Young

Context: Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY) in most populations. India currently has the largest number of people with diabetes in the world, and onset of type 2 diabetes occurs at a younger age with possible overlap with MODY. There are very few data on MODY mutations from India. Objective: The objective was to screen coding and promoter regions of HNF1A gene for mutations in unrelated South Indian subjects in whom a clinical diagnosis of MODY was made. Design: This was an observational cross-sectional study. Setting: The study was conducted at a diabetes specialties centre in Chennai in southern India. Patients: Ninety-six unrelated south Indian subjects in whom clinical diagnosis of MODY was made were included in the study. The control population comprised of 57 unrelated nondiabetic subjects selected from the Chennai Urban Rural Epidemiology Study, a study conducted on a representative population (aged >= 20 yr) of Chennai. Results: We identified nine novel variants comprising seven mutations (one novel mutation -538G>C at promoter region and six novel coding region mutations) and two polymorphisms in the HNF1A gene. Functional studies revealed reduced transcriptional activity of the HNF1A promoter for two promoter variants. We also observed cosegregation with diabetes of the Arg263His coding region mutation in eight members of one MODY family, whereas it was absent in nondiabetic subjects of this family. Conclusion: This study suggests that mutations in the HNF1A gene comprise about 9% of clinically diagnosed MODY subjects in southern India and a novel Arg263His mutation cosegregates with MODY in one family. (J Clin Endocrinol Metab 94: 1959-1965, 2009)