A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes
A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes
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IRS1 的错义突变与早发 2 型糖尿病的发生有关
DOI：
10.1155/2020/9569126
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发表时间：
2020-01-25
影响因子：
2.8
通讯作者：
Deng, Aiping
中科院分区：
文献类型：
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作者：
Li, Juyi;Sun, Shan;Deng, Aiping
单基因糖尿病和早发性2型糖尿病可能存在重叠。对早发性糖尿病的准确诊断对于了解糖尿病的发病机制和选择最佳治疗方法具有重要价值。青壮年起病的糖尿病(MODY)的致病基因多数在中国尚不清楚。在这项研究中，登记了一个疑似MODY的家庭。用全外显子测序(WES)分析先证者的变异。根据变异的频率、位置、功能结果和生物信息学软件进行筛选。候选致病变异体通过Sanger测序进行验证，并在该家族的其他成员和无关的健康对照中进行共隔离测试。使用DAVID(数据库注释、可视化和集成发现)和STRING在线分析工具对候选致病基因进行KEGG(京都基因和基因组百科全书)和PPI(蛋白质相互作用)分析。在WES中共发现123291个变异，包括105344个SNPs和17947个Indels。在糖尿病基因中发现了一个可能致病的罕见错义杂合子突变(c.2137C >； T，irs1中的p.His713Tyr)，该突变是该家族中的一个共分离基因，而不是在无关的健康对照中。该突变在该基因的氨基酸序列中的位置在物种之间高度保守。Bta04930、II型糖尿病(GCK、INS、PDX1、ABCC8、IRS1)和bta04910、胰岛素信号通路(GCK、INS、IRS1)。PPI分析表明，IRS1与INS、KCNJ11、GCK等3种已知致病蛋白相互作用。我们得出结论，WES可能是早发性糖尿病患者基因检测的初始选择。IRS1 p.His713Tyr可能是单基因糖尿病的致病突变，这可能需要进一步的验证，而IRS1 p.His713Tyr影响糖尿病发生发展的确切分子机制仍有待进一步的前瞻性研究确定。
There could be an overlap of monogenic diabetes and early-onset type 2 diabetes mellitus. Precise diagnosis of early-onset diabetes has proven valuable for understanding the mechanism of diabetes and selecting optimal therapy. The majority of maturity onset diabetes of the young (MODY) pathogenic genes in China is still unknown. In this study, a family with suspected MODY was enrolled. Whole-exome sequencing (WES) was used to analyze the variants of the proband. Variants were filtered according to their frequency, location, functional consequences, and bioinformatics software. Candidate pathogenic variants were validated by Sanger sequencing and tested for cosegregation in other members of the family and nonrelated healthy controls. KEGG (Kyoto Encyclopedia of Genes and Genomes) and PPI (protein-protein interaction) analysis were conducted using the DAVID (Database for Annotation, Visualization, and Integrated Discovery) and the STRING online analysis tools for the candidate pathogenic gene. A total of 123291 variants including 105344 SNPs and 17947 InDels were found in WES. A likely pathogenic rare missense heterozygous mutation in diabetes genes (c.2137C > T, p.His713Tyr in IRS1) was identified, which was a cosegregate in this family and not in nonrelated healthy controls. The position of the mutation in the aminoacid sequence of the gene is highly conserved among the species. 2 significantly enriched KEGG pathways were identified including bta04930, type II diabetes mellitus (GCK, INS, PDX1, ABCC8, and IRS1), and bta04910, insulin signaling pathway (GCK, INS, and IRS1). PPI analysis displayed that IRS1 interacts with 3 known pathogenic proteins including INS, KCNJ11, and GCK. We conclude that WES could be an initial option for genetic testing in patients with early-onset diabetes. IRS1 p.His713Tyr is implicated as a possible pathogenic mutation in monogenic diabetes, which might require further validation, and the precise molecular mechanism underlying the influence of IRS1 p.His713Tyr on the development of diabetes remains to be determined in the further prospective studies.