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Clin Genet. 2016 Dec;90(6):486-495. doi: 10.1111/cge.12757. Epub 2016 Mar 4.

Structure-function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes.

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Department of Molecular genetics, Madras Diabetes Research Foundation, ICMR Advanced Centre for Genomics of Type 2 Diabetes and Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention & Control, IDF Centre of Education, Chennai, India.
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Biomedicine, University of Bergen, Bergen, Norway.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.


Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by onset of diabetes below 25 years of age, autosomal dominant mode of inheritance and primary defect in insulin secretion. Mutations in the gene (HNF1A) encoding transcription factor hepatocyte nuclear factor 1A (HNF-1A) results in one of the most common forms of MODY (MODY3). HNF-1A is mainly enriched in pancreatic β-cells and hepatocytes and important for organ development and normal pancreatic function. We here report on the functional interrogation of eight missense HNF1A mutations associated with MODY3 in South Indian subjects, and the contributing effect of common variant (S487N) within HNF1A. Of the eight mutations, three mutations (p.R171G, p.G245R and p.R263H), in particular, affected HNF-1A function in transfected HeLa cells by reducing both transcriptional activity and nuclear localization, possibly due to disruption of the integrity of the three dimensional structure. The common variant p.S487N contributed further to the loss-of-function of p.R271Q (p.R271Q+p.S487N double mutant), in vitro, on both activity and localization. Our data on the first functional study of HNF1A mutations in South India subjects confers that the defect of the HNF-1A mutant proteins are responsible for MODY3 diabetes in these patients.


HNF1A gene mutations; MODY; South India; functional characterization

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