| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Kazuma Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (60292215)
HINOKIO Yoshinori Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (10282071)
KATAGIRI Hedeki Tohoku University Graduate School of Medicine, Division of Advanced Therapeutics for Metabolism and Diabetes, Professor, 大学院・医学系研究科, 教授 (00344664)
ISHIHARA Hisamitsu Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手
HIRAI Masashi Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (80312578)
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| Research Abstract |
Wolfram syndrome is an autosomal recessive disorder associated with juvenile onset diabetes mellitus, optic atrophy, sensorineural deafness and diabetes insipidus. We identified, employing positional cloning, a gene responsible for this disorder and designated it WFS1. We also showed WFS1 protein to be localized in the ER membrane. In addition, WFS1 shares some sequence similarity with yeast Hrd3p, which is involved in ER-associated degradation of malfolded proteins. Thus, though WFS1 protein appears to play a role in the ER-stress response, its precise function remains to be clarified. To elucidate the functions of this novel protein and the pathophysiology of Wolfram syndrome, we have generated mice lacking the WFS1 gene (WFS1-KO). WFS1-KO mice are normal in appearance, growth and fertility Blood glucose levels in male WFS1-KO mice start to rise at around 12 weeks and are significantly higher than those of wild-type mice at 24 weeks (267±33 vs 146±34 mg/dl). This is associated with loss of islet β cells; whole pancreatic insulin content in WFS1-KO mice was 30-times lower than that in wild-type mice (11±4 vs 287±34 ng/mg pancreas). Immunohistochemical analysis of the pancreas using an anti-WFS1 protein antibody revealed that WFS1 protein is absent from exocrine tissue, but is strongly expressed in endocrine β cells. WFS1 protein is not expressed in glucagon-positive cells and the majority of somatostatin-, and pancreatic polypeptide-positive cells are devoid of WFS1 immunoreactivity. In WFS1-KO mice, β cell number fell with age, while a cells were somewhat increased and were scattered throughout the islet. These results strongly suggest WFS1 protein to play a critical role in survival and/or regeneration of β cells and progressive loss of islet β cells to be the major cause of diabetes in this disorder.
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