Monognnic 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...Monognnic 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 heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-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 IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.展开更多
文摘Monognnic 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 heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, p.Ala2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-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 IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.
