• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Elucidation of molecular pathophysiology and development of the methods for molecular diagnosis of the disease associated with WFS1 gene mutations.

Research Project

Project/Area Number 11557012
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Pathological medical chemistry
Research InstitutionYamaguchi University

Principal Investigator

TANIZAWA Yukio  Yamaguchi University, Hospital, Assistant professor, 医学部・附属病院, 講師 (00217142)

Co-Investigator(Kenkyū-buntansha) MATSUBARA Atsushi  Yamaguchi University, Hospital, Instructor of Medicine, 医学部・附属病院, 助手 (40311815)
INOUE Hiroshi  Yamaguchi University, Hospital, Instructor of Medicine, 医学部・附属病院, 助手 (20294639)
UEDA Kohei  Yamaguchi University, Hospital, Instructor of Medicine, 医学部・附属病院, 助手 (50325221)
0HTA Yasuharu  Yamaguchi University, Hospital, Clinical Fellow, 医学部・附属病院, 講師(臨床)
TAKEDA Komei  Yamaguchi University, Hospital, Clinical Fellow, 医学部・附属病院, 医員(臨床)
亀井 信二  山口大学, 医学部, 助手 (30314800)
青木 稔  山口大学, 医学部, 助手 (70304475)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2001: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1999: ¥6,700,000 (Direct Cost: ¥6,700,000)
KeywordsWolfram Syndrome / Diabetes Mellitus / Endoplasmic Reticulum / Mutation / ER stress / Optic Atrophy / 遺伝子 / 難聴 / in situ hybridization
Research Abstract

Wolfram (DIDMOAD) syndrome is an autosomal recessive disorder accompanied by juvenile-onset insulin-dependent diabetes mellitus and progressive optic atrophy. We recently identified the WFS1 (Wolfram syndrome 1) gene, a novel gene of unknown function. In this study, we generated a specific antibody against the COOH terminus of the WFS1 protein and investigated its subcellular localization in cultured cells. We also studied its distributions in rat brain. Biochemical studies indicated the WFS1 protein to be an integral, endoglycosidase H-sensitive membrane glycoprotein that localizes primarily in the endoplasmic reticulum. Consistent with this, immunofluorescence cell staining of WFS1 showed a characteristic reticular pattern over the cytoplasm and nuclear envelope. No evidence of co-localization of WFS1 with mitochondria was obtained, arguing against an earlier clinical hypothesis that Wolfram syndrome is a mitochondria-mediated disorder. In rat brain, WFS1 was found to be present pred … More ominantly in selected neurons in the hippocampus CA1, amygdaloid areas, olfactory tubercle and superficial layer of the allocortex. These expression sites, that is, components of the limbic system or structures closely associated with this system, may be involved in the psychiatric, behavioral and emotional abnormalities characteristic of this syndrome. ER localization of WFS1 suggests this protein to play as yet undefined roles in membrane trafficking, protein processing, and/or regulation of ER calcium homeostasis.
As a step to elucidate the function of WFS1, we created a WFS1 -/- mice. In addition, we established WFS1 -/- mouse embryonic fibroblast from these mice. The studies for understanding the roles of WFS1 are being undertaken at whole body (mice) and cellular levels.
We also studied the possible involvement of WFS1 gene mutations in the development of type 1 diabetes mellitus. We screened for the mutations in 21 Japanese patients with non-immune type 1 diabetes mellitus. Several nucleotide substitutions (single nucleotide polymorphisms) were identified without obvious association with this form of diabetes. Less

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Takeda K: "WFS1(Wolfram syndrome 1)gene product : predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain"Human Molecular Genetics. 10. 477-484 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 谷澤 幸生: "Wolfram症候群遺伝子(WFS1)のポジショナルクローニング"臨床病理(Jpn J Clin Pathol). 48(10). 941-947 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 谷澤 幸生: "Wolfram症候群遺伝子のポジショナルクローニング"遺伝子医学. 4(2). 313-317 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuya S: "Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis"Endocrinology. 142. 4827-4830 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine stimulated insulin secretion"Diabetes. 51(in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuo M: "Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemichypoglycemia of infancy"J Biol Chem. 275. 41184-41191 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Genetic Analysis or Japanese Patients with Persistent Hyperinsulinemic Hypoglycemia o Infancy. NBF-2 mutation impairs cooperative binding or adenine nucleotides to SUR1"Diabetes. 49. 114-120 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 井上 寛: "分子糖尿病学の進歩2000(Wolfram(DIDMOAD)症候群の原因遺伝子の同定)"金原出版. 196 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takeda K: "WFS1 (Wolfram syndrome 1) gene product : predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain"Hum Mol Genet. 10. 477-484 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Genetic analysis of Japanese patients with persisten hyperinsulinemic hypoglycemia of infancy. NBF-2 mutation impairs cooperative binding of adenine nucleotides to SUR1"Diabetes. 49. 114-120 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuo M: "Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy"J Biol Chem. 275. 41184-41191 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuya S: "Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis"Endocrinol. 142. 4827-4830 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Unregulated elevation of glutamate dehydrogenase activity induces exaggerated glutamine-stimulated insulin secretion : Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH"Diabetes. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Posotional cloning for the gene (WFS1) for Wolfram Syndrome"Jpn J Clin Pathol. 48. 941-947 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanizawa Y: "Positional cloning of Wolfram syndrome gene (WFS1)"Gene and Medicine. 4. 313-317 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takeda K: "WFS1 (Wolfram syndrome 1) gene product : predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain"Human Molecular Genetics. 10. 477-484 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okuya S: "Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis"Endocrinology. 142. 4827-4830 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanizawa Y: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine stimulated insulin secretion"Diabetes. 51(In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Emoto M: "Troglitazone Treatment Increases Plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 Adipocytes"Diabetes. 50. 1166-1170 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda K: "WFS1 (Wolfram syndrome 1) gene product : predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain."Human Molecular Genetics. 10. 477-484 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuo M: "Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy."J Biol Chem. 275. 41184-41191 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanizawa Y: "Genetic Analysis of Japanese Patients with Persistent Hyperinsulinemic Hypoglycemia o Infancy. NBF-2 mutation impairs cooperative binding of adenine nucleotides to SUR1"Diabetes. 49. 114-120 (2000)

    • Related Report
      2000 Annual Research Report

URL: 

Published: 1999-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi