Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10

• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2017,（5）
• 页码范围: 376-383
• 页数: 8页
• 语种: 英文
• DOI: 10.1093/jmcb/mjx039

摘要

Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics.This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms.Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes.One novel heterozygous mutation (p.Ala2Thr) in INS was identified.It was further genotyped in an additional case-control population (6523 cases and 4635 controls),and this variant was observed in 0.09％ of cases.Intracellular trafficking of insulin proteins was assessed in INS1-E and HEK293T cells,p.Ala2Thr preproinsulin-GFP was markedly retained in the endoplasmic reticulum (ER) in INS1-E cells.Activation of the PERK-elF2α-ATF4,IRE1α-XBP1,and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant.In conclusion,we identified a causative mutation in INS responsible for maturity-onset diabetes of the young 10 (MODY10) in a Chinese population and demonstrated that this mutation affected β cell function by inducing ER stress.