Human Molecular Genetics Advance Access published online on March 31, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh125
© 2004 by Oxford University Press
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1 Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
* To whom correspondence should be addressed. E-mail: oka{at}int3.med.tohoku.ac.jp.
Wolfram syndrome, an autosomal recessive disorder, characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. In order to gain insight into the pathophysiology of this disease, we disrupted the WFS1 gene in mice. The mutant mice developed glucose intolerance or overt diabetes due to insufficient insulin secretion in vivo. Islets isolated from mutant mice exhibited a decrease in insulin secretion in response to glucose. The defective insulin secretion was accompanied by reduced cellular calcium responses to the secretagogue. Immunohistochemical analyses with morphometry and measurement of whole pancreas insulin content demonstrated progressive
Article
Disruption of the WFS1 gene in mice causes progressive
-cell loss and impaired stimulus-secretion coupling in insulin secretion
2 Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Tokushima, Japan
3 Division of Diabetes and Endocrinology, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan
4 Division of Immunology and Embryology, Tohoku University Graduate School of Medicine, Sendai, Japan
5 Division of Advanced Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
6 Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Japan
7 Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
Abstract 
-cell loss in mutant mice, while the 
-cell, which barely expresses WFS1 protein, was preserved. Furthermore, isolated islets from mutant mice exhibited an increased apoptosis, as assessed by DNA fragment formation, at a high concentration of glucose or with exposure to endoplasmic reticulum-stress inducers. These results strongly suggest that WFS1 protein plays an important role in both stimulus-secretion coupling for insulin exocytosis and the maintenance of -cell mass, deterioration of which leads to impaired glucose homeostasis. These WFS1 mutant mice provide a valuable tool for better understanding the pathophysiology of Wolfram syndrome as well as WFS1 function.
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