A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes
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 ge...
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | International Journal of Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2020/9569126 |
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| author | Juyi Li Shan Sun Xiufang Wang Yarong Li Hong Zhu Hongmei Zhang Aiping Deng |
| author_facet | Juyi Li Shan Sun Xiufang Wang Yarong Li Hong Zhu Hongmei Zhang Aiping Deng |
| author_sort | Juyi Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0e838795a41a4bb9895cff84eff78190 |
| institution | OA Journals |
| issn | 1687-8337 1687-8345 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Endocrinology |
| spelling | doaj-art-0e838795a41a4bb9895cff84eff781902025-08-20T02:01:40ZengWileyInternational Journal of Endocrinology1687-83371687-83452020-01-01202010.1155/2020/95691269569126A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 DiabetesJuyi Li0Shan Sun1Xiufang Wang2Yarong Li3Hong Zhu4Hongmei Zhang5Aiping Deng6Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of General Practice, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of Pain, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of General Practice, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 21 Shengli Road, 430021 Wuhan, Hubei, ChinaThere 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.http://dx.doi.org/10.1155/2020/9569126 |
| spellingShingle | Juyi Li Shan Sun Xiufang Wang Yarong Li Hong Zhu Hongmei Zhang Aiping Deng A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes International Journal of Endocrinology |
| title | A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes |
| title_full | A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes |
| title_fullStr | A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes |
| title_full_unstemmed | A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes |
| title_short | A Missense Mutation in IRS1 is Associated with the Development of Early-Onset Type 2 Diabetes |
| title_sort | missense mutation in irs1 is associated with the development of early onset type 2 diabetes |
| url | http://dx.doi.org/10.1155/2020/9569126 |
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