Human Molecular Genetics Advance Access originally published online on March 31, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 11 1159-1170
DOI: 10.1093/hmg/ddh125
Human Molecular Genetics, Vol. 13, No. 11 © Oxford University Press 2004; all rights reserved
Disruption of the WFS1 gene in mice causes progressive ß-cell loss and impaired stimulus–secretion coupling in insulin secretion
1Division of Molecular Metabolism and Diabetes, 2Division of Immunology and Embryology, and 3Division of Advanced Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan, 4Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Tokushima, Japan, 5Division of Diabetes and Endocrinology, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan and 6Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Japan
Received February 8, 2004; Accepted March 26, 2004
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 ß-cell loss in mutant mice, while the 
-cell, which barely expresses WFS1 protein, was preserved. Furthermore, isolated islets from mutant mice exhibited increased apoptosis, as assessed by DNA fragment formation, at 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 maintenance of ß-cell mass, deterioration of which leads to impaired glucose homeostasis. These WFS1 mutant mice provide a valuable tool for understanding better the pathophysiology of Wolfram syndrome as well as WFS1 function.
* To whom correspondence should be addressed at: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Tel: +81 227177173; Fax: +81 227177179; Email: oka{at}int3.med.tohoku.ac.jp
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