Li Juyi, Sun Shan, Wang Xiufang, Li Yarong, Zhu Hong, Zhang Hongmei, Deng Aiping
Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, China.
Department of General Practice, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, China.
Int J Endocrinol. 2020 Jan 25;2020:9569126. doi: 10.1155/2020/9569126. eCollection 2020.
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 ) 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 (, , , , and ), and bta04910, insulin signaling pathway (, , and ). 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. 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 p.His713Tyr on the development of diabetes remains to be determined in the further prospective studies.
单基因糖尿病与早发型2型糖尿病可能存在重叠。早发型糖尿病的准确诊断已被证明对理解糖尿病机制和选择最佳治疗方法具有重要价值。中国大多数青年发病的成年型糖尿病（MODY）致病基因仍不清楚。在本研究中，纳入了一个疑似MODY的家系。采用全外显子组测序（WES）分析先证者的变异。根据变异的频率、位置、功能后果和生物信息学软件对变异进行筛选。候选致病变异通过桑格测序进行验证，并在该家系的其他成员和无关健康对照中进行共分离检测。使用DAVID（注释、可视化和综合发现数据库）和STRING在线分析工具对候选致病基因进行KEGG（京都基因与基因组百科全书）和PPI（蛋白质-蛋白质相互作用）分析。在WES中总共发现了123291个变异，包括105344个单核苷酸多态性（SNP）和17947个插入缺失（InDel）。在糖尿病基因中鉴定出一个可能致病的罕见错义杂合突变（c.2137C＞T，p.His713Tyr），该突变在这个家系中呈共分离，而在无关健康对照中未出现。该基因氨基酸序列中的突变位置在物种间高度保守。鉴定出2条显著富集的KEGG通路，包括bta04930，II型糖尿病（，，，，和），以及bta04910，胰岛素信号通路（，，和）。PPI分析显示，胰岛素受体底物1（IRS1）与3种已知致病蛋白相互作用，包括胰岛素（INS）、内向整流型钾通道蛋白11（KCNJ11）和葡萄糖激酶（GCK）。我们得出结论，WES可能是早发型糖尿病患者基因检测的首选方法。p.His713Tyr被认为是单基因糖尿病中一个可能的致病突变，这可能需要进一步验证，并且p.His713Tyr对糖尿病发生发展影响的精确分子机制仍有待在进一步的前瞻性研究中确定。
