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.
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.
J Mol Cell Biol. 2017 Oct 1;9(5):376-383. doi: 10.1093/jmcb/mjx039.
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.
单基因糖尿病常因重叠特征而被误诊为 2 型糖尿病。本研究旨在发现临床诊断为 2 型糖尿病患者中单基因糖尿病的新致病突变，并探讨潜在的分子机制。对 31 名临床诊断为 2 型糖尿病的个体进行全外显子组测序。在 INS 中发现了一个新的杂合突变（p.Ala2Thr）。该突变进一步在另外一个病例对照人群（6523 例病例和 4635 例对照）中进行了基因分型，该变异在 0.09%的病例中观察到。在 INS1-E 和 HEK293T 细胞中评估了胰岛素蛋白的细胞内转运。p.Ala2Thr 前胰岛素-GFP 在 INS1-E 细胞中明显滞留在内质网（ER）中。在转染 p.Ala2Thr 突变的 INS1-E 细胞中检测到 PERK-eIF2α-ATF4、IRE1α-XBP1 和 ATF6 途径的激活以及 ER 伴侣蛋白的上调。总之，我们在中国人群中发现了 INS 中的一个致病突变，该突变导致青年起病的成年型糖尿病 10 型（MODY10），并证明该突变通过诱导 ER 应激影响β细胞功能。
