Journal Article

Disruption of the <i>WFS1</i> gene in mice causes progressive β-cell loss and impaired stimulus–secretion coupling in insulin secretion

Hisamitsu Ishihara, Satoshi Takeda, Akira Tamura, Rui Takahashi, Suguru Yamaguchi, Daisuke Takei, Takahiro Yamada, Hiroshi Inoue, Hiroyuki Soga, Hideki Katagiri, Yukio Tanizawa and Yoshitomo Oka

in Human Molecular Genetics

Volume 13, issue 11, pages 1159-1170
Published in print June 2004 | ISSN: 0964-6906
Published online March 2004 | e-ISSN: 1460-2083 | DOI:
Disruption of the WFS1 gene in mice causes progressive β-cell loss and impaired stimulus–secretion coupling in insulin secretion

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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 β-cell loss in mutant mice, while the α-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 β-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.

Journal Article.  6121 words.  Illustrated.

Subjects: Genetics and Genomics

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