Abstract
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.
Highlights
Introduction ere were415 million people living with diabetes worldwide in 2015, and this number will rise to 642 million in 2040 and about 193 million people still undiagnosed [1]
IRS1 acts as a docking protein between the insulin receptor and multiple Src homology-2- (SH2-) containing proteins in the insulin signaling cascade, which plays a key role in modulating tissue response to insulin [17, 18]
Several genetic variants had been identified in human IRS1, which were associated with insulin resistance and diabetes susceptibility, Gly(972)Arg variant [23,24,25,26,27,28,29]
Summary
Introduction ere were415 million people living with diabetes worldwide in 2015, and this number will rise to 642 million in 2040 and about 193 million people still undiagnosed [1]. Patients with early-onset diabetes are more likely to have a positive family history of diabetes [4]. There could be an overlap between monogenic diabetes belonging to specific disease forms and early-onset diabetes mellitus in International Journal of Endocrinology those who are diagnosed at an age younger than 30 years and positive parental history of diabetes [5]. MODY is estimated to make up approximately 1-2% of all diabetes and is difficult to distinguish T1DM from T2DM [7]. It is estimated that more than 80% of MODY are currently undiagnosed or misdiagnosed as T1DM or T2DM [8, 9]. A majority of Chinese MODY people are due to the defection of unknown genes [10]; the screening of pathogenic genes in diabetic families and the appropriate treatment choice will be of great significance, especially in China
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