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Nat Commun. 2015 Apr 7;6:6748. doi: 10.1038/ncomms7748.

Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.

Author information

1
1] Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan [2] Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan [3] Department of Hepatology, Diabetes and Endocrinology, School of Medicine, Saga University, Saga 849-8501, Japan.
2
Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
3
Department of Diabetes and Genes, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
4
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
5
Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
6
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
7
Department of Molecular Anatomy, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
8
Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
9
Department of Hepatology, Diabetes and Endocrinology, School of Medicine, Saga University, Saga 849-8501, Japan.
10
Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health, 7-6 Nagare, Tsujimachi, Kita-ku, Nagoya, Aichi 462-8576, Japan.
11
Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.

Abstract

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.

PMID:
25849081
PMCID:
PMC4396380
DOI:
10.1038/ncomms7748
[Indexed for MEDLINE]
Free PMC Article

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