Human Molecular Genetics Advance Access originally published online on March 31, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-F. Chen, C.-H. Kao, Y.-T. Chen, C.-H. Wang, C.-Y. Wu, C.-Y. Tsai, F.-C. Liu, C.-W. Yang, Y.-H. Wei, M.-T. Hsu, et al. Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice Genes & Dev., May 15, 2009; 23(10): 1183 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Koks, U. Soomets, J. L. Paya-Cano, C. Fernandes, H. Luuk, M. Plaas, A. Terasmaa, V. Tillmann, K. Noormets, E. Vasar, et al. Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway Physiol Genomics, May 13, 2009; 37(3): 249 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Zalloua, S. T. Azar, M. Delepine, N. J. Makhoul, H. Blanc, M. Sanyoura, A. Lavergne, K. Stankov, A. Lemainque, P. Baz, et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon Hum. Mol. Genet., December 15, 2008; 17(24): 4012 - 4021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Imai, H. Katagiri, T. Yamada, Y. Ishigaki, T. Suzuki, H. Kudo, K. Uno, Y. Hasegawa, J. Gao, K. Kaneko, et al. Regulation of Pancreatic {beta} Cell Mass by Neuronal Signals from the Liver Science, November 21, 2008; 322(5905): 1250 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Scheuner and R. J. Kaufman The Unfolded Protein Response: A Pathway That Links Insulin Demand with {beta}-Cell Failure and Diabetes Endocr. Rev., May 1, 2008; 29(3): 317 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Eizirik, A. K. Cardozo, and M. Cnop The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus Endocr. Rev., February 1, 2008; 29(1): 42 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zatyka, C. Ricketts, G. da Silva Xavier, J. Minton, S. Fenton, S. Hofmann-Thiel, G. A Rutter, and T. G. Barrett Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress Hum. Mol. Genet., January 15, 2008; 17(2): 190 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cano, L. Molines, R. Valero, G. Simonin, V. Paquis-Flucklinger, B. Vialettes, and the French Group of Wolfram Syndrome Microvascular Diabetes Complications in Wolfram Syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness [DIDMOAD]): An age- and duration-matched comparison with common type 1 diabetes Diabetes Care, September 1, 2007; 30(9): 2327 - 2330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hasegawa, T. Ogihara, T. Yamada, Y. Ishigaki, J. Imai, K. Uno, J. Gao, K. Kaneko, H. Ishihara, H. Sasano, et al. Bone Marrow (BM) Transplantation Promotes {beta}-Cell Regeneration after Acute Injury through BM Cell Mobilization Endocrinology, May 1, 2007; 148(5): 2006 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamada, H. Ishihara, A. Tamura, R. Takahashi, S. Yamaguchi, D. Takei, A. Tokita, C. Satake, F. Tashiro, H. Katagiri, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic {beta}-cells Hum. Mol. Genet., May 15, 2006; 15(10): 1600 - 1609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Fonseca, M. Fukuma, K. L. Lipson, L. X. Nguyen, J. R. Allen, Y. Oka, and F. Urano WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic {beta}-Cells J. Biol. Chem., November 25, 2005; 280(47): 39609 - 39615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ueda, J. Kawano, K. Takeda, T. Yujiri, K. Tanabe, T. Anno, M. Akiyama, J. Nozaki, T. Yoshinaga, A. Koizumi, et al. Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic {beta}-cells via transcriptional activation Eur. J. Endocrinol., July 1, 2005; 153(1): 167 - 176. [Abstract] [Full Text] [PDF]
|
|