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Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10 Free
Jing Yan1,†, Feng Jiang1,†, Rong Zhang1, Tongfu Xu2, Zhou Zhou1, Wei Ren1, Danfeng Peng1, Yong Liu2, Cheng Hu1,3,*, and Weiping Jia1,*
1 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong
University Affiliated Sixth People’s Hospital, Shanghai, China
2 The Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
University of the Chinese Academy of Sciences, Shanghai, China
3 Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China † These authors contributed equally to this work. *Correspondence to:Cheng Hu, E-mail: alfredhc@sjtu.edu.cn; Weiping Jia, E-mail: wpjia@sjtu.edu.cn
J Mol Cell Biol, Volume 9, Issue 5, October 2017, 376-383,  https://doi.org/10.1093/jmcb/mjx039
Keyword: whole-exome sequencing, causative mutation, MODY10, endoplasmic reticulum stress

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–eIF2α–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.


Volume 9, Issue 5
October 2017