Premium
Structure–function studies of HNF1A ( MODY3 ) gene mutations in South Indian patients with monogenic diabetes
Author(s) -
Balamurugan K.,
Bjørkhaug L.,
Mahajan S.,
Kanthimathi S.,
Njølstad P.R.,
Srinivasan N.,
Mohan V.,
Radha V.
Publication year - 2016
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12757
Subject(s) - hnf1a , missense mutation , hepatocyte nuclear factors , biology , maturity onset diabetes of the young , genetics , gene , loss function , mutation , mutant , phenotype , transcription factor , endocrinology , medicine
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.