Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family
Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family
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中国MODY10家族胰岛素基因Ala2Thr突变的鉴定
DOI：
10.1007/s11010-020-03748-0
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发表时间：
2020-05-13
影响因子：
4.3
通讯作者：
Liu, Limei
中科院分区：
文献类型：
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作者：
Zhang, Juan;Liu, Yanjun;Liu, Limei
在中国，超过80%的年轻人的成熟型糖尿病（MODY）是遗传原因不明的。为探讨胰岛素基因（insulin gene，INS）突变是否与部分中国人MODY的发病有关，我们对56例MODY家系先证者进行了INS突变的筛查，并探讨了MODY 10的致病机制。对所鉴定的INS突变进行结构-功能表征和临床分析。在一个MODY家系中发现了一个INS突变，即2位丙氨酸-苏氨酸取代（A2 T），并与高血糖共分离。A2 T突变使前胰岛素原信号肽（SP）N端的α-螺旋转变为β-折叠。A2 T突变不影响前胰岛素原跨内质网（ER）膜的转运，但损害其SP在ER内的切割。在用A2 T突变体转染的INS-1细胞中，葡萄糖刺激的胰岛素分泌（GSIS）显著降低，而BiP荧光素酶活性与野生型（WT）相比显著增加。我们在一个中国MODY家系中发现了一个与糖尿病共分离的INS-A2 T突变。该突变严重损害SP裂解，从而阻断胰岛素原的形成，导致增强的ER应激，这可能是导致胰岛素分泌减少和随后MODY 10发病的原因。
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 screenedINSmutations causing MODY10 in MODY pedigrees and explored the potential pathogenic mechanisms.INSmutations were screened in 56 MODY familial probands. Structure–function characterization and clinical profiling of identifiedINSmutations were conducted. AnINSmutation, 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.