Journal
JOURNAL OF MOLECULAR CELL BIOLOGY
Volume 9, Issue 5, Pages 376-383Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjx039
Keywords
whole-exome sequencing; causative mutation; MODY10; endoplasmic reticulum stress
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Funding
- National Key Research and Development Program [2016YFC0903303]
- National Science Foundation of China [81170735, 81322010, 31500955]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20152527]
- National Program for Support of Top-notch Young Professionals
- State Key Laboratory of Medical Genomics, Outstanding Academic Leaders of Shanghai Health System [2017BR008]
- Shanghai Sailing Program [14YF1412000]
- Innovation Fund for PhD Students from Shanghai Jiao Tong University School of Medicine [BXJ201632]
- Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine [15ZH4006]
- Shanghai SJTUSM Biobank
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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-eIF2 alpha-ATF4, IRE1 alpha-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 beta cell function by inducing ER stress.
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