Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family.,Molecular and Cellular Biochemistry

当前位置： X-MOL 学术 › Mol. Cell. Biochem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family.
Molecular and Cellular Biochemistry ( IF 3.5 ) Pub Date : 2020-05-13 , DOI: 10.1007/s11010-020-03748-0
Juan Zhang ₁ , Yanjun Liu _{2,

3} , Ming Li ₁ , Xiaoxu Ge ₄ , Ying Wang ₅ , Xin Huang ₆ , Di Yang ₇ , Rong Zhang ₁ , Yating Chen ₁ , Ming Lu ₈ , Jun Yin ₁ , Mingqiang Song ₉ , Yongfeng Wang ₁₀ , Yanzhong Wang ₁₁ , Feng Wang ₁₂ , Meisheng Jiang ₁₃ , Limei Liu ₁

Affiliation

Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA.
David Geffen School of Medicine at University of California, Los Angeles, USA.
Department of Endocrinology, School of Medicine, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
School of Medicine, Magee-Womens Research Institute, University of Pittsburgh, 204 Craft Ave., Pittsburgh, PA, 15213, USA.
Department of Nutritional Science and Toxicology, University of California at Berkeley, Berkeley, USA.
Department of Endocrinology & Metabolism, Putuo Hospital Attached to Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200000, China.
Department of Endocrinology, Weihai Municipal Hospital, No. 70, Heping Road, Weihai, 264200, China.
Department of Endocrinology, Xianxian Hospital of Traditional Chinese Medicine, Cangzhou City, Hebei Province, China.
School of Population Health and Environmental Science, King's College London, London, UK.
Department of Nephrology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.

More than 80% of maturity-onset diabetes of the young (MODY) in Chinese is genetically unexplained. To investigate whether the insulin gene (INS) mutation is responsible for some Chinese MODY, we screened INS mutations causing MODY10 in MODY pedigrees and explored the potential pathogenic mechanisms. INS mutations were screened in 56 MODY familial probands. Structure-function characterization and clinical profiling of identified INS mutations were conducted. An INS mutation, at the position 2 alanine-to-threonine substitution (A2T), was identified and co-segregated with hyperglycemia in a MODY pedigree. The A2T mutation converted an α-helix into a β-sheet at the N-terminal of the signal peptide (SP) of preproinsulin. The A2T mutation did not affect preproinsulin translocation across endoplasmic reticulum (ER) membrane, but impaired its SP cleavage within the ER. In INS-1 cells transfected with an A2T mutant, glucose-stimulated insulin secretion (GSIS) was significantly decreased, while BiP luciferase activities were significantly increased compared to that of wild type (WT). We identified an INS-A2T mutation cosegregating with diabetes in a Chinese MODY pedigree. This mutation severely impaired SP cleavage and thus blocked the formation of proinsulin, resulting in enhanced ER stress, which may be responsible for decreased insulin secretion and subsequently, the onset of MODY10.

更新日期：2020-05-13

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11