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.
Mol Cell Biochem. 2020 Jul;470(1-2):77-86. doi: 10.1007/s11010-020-03748-0. Epub 2020 May 13.
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.
在中国，超过 80%的青年发病型糖尿病（MODY）的遗传原因尚不清楚。为了研究胰岛素基因（INS）突变是否导致了一些中国 MODY，我们在 MODY 家系中筛查了导致 MODY10 的 INS 突变，并探索了潜在的致病机制。我们对 56 名 MODY 家系的先证者进行了 INS 突变筛查。对鉴定出的 INS 突变进行了结构-功能特征分析和临床特征分析。在一个 MODY 家系中发现了一个 INS 突变，即 2 位丙氨酸到苏氨酸取代（A2T），该突变与高血糖共分离。A2T 突变将前胰岛素原信号肽（SP）N 端的α-螺旋转化为β-折叠。A2T 突变不影响前胰岛素原穿过内质网（ER）膜的易位，但会损害其在 ER 内的 SP 切割。与野生型（WT）相比，在转染 A2T 突变体的 INS-1 细胞中，葡萄糖刺激的胰岛素分泌（GSIS）显著降低，而 BiP 荧光素酶活性显著增加。我们在一个中国 MODY 家系中鉴定出了与糖尿病共分离的 INS-A2T 突变。该突变严重损害了 SP 的切割，从而阻止了前胰岛素的形成，导致内质网应激增强，这可能是胰岛素分泌减少进而导致 MODY10 发病的原因。
