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The HNF-related transcription cascade in maturity-onset diabetes of the young.

Research Project

Project/Area Number 11671104
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionTohoku University

Principal Investigator

HINOKIO Yoshinori  Tohoku University, University Hospital, Research Associate, 医学部・附属病院, 助手 (10282071)

Co-Investigator(Kenkyū-buntansha) HIRAI Masashi  Tohoku University, University Hospital, Research Associate, 医学部・附属病院, 助手 (80312578)
SUZUKI Susumu  Tohoku University, University Hospital, Lecturer, 医学部・附属病院, 講師 (70216399)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsMODY / HNF / gene mutations / 糖尿病 / MODY
Research Abstract

Recent genetic studies have shown that maturity-onset diabetes of the young (MODY) is a heterogeneous disorder that can result from mutations in the hepatocyte nuclear factor (HNF)-1α/MODY3, 1β/MODY5, 4α/MODY1 and glucokinase/MODY2 genes. An upstream regulators of HNF-4α expression could be necessary for normal pancreatic β cell function and metabolism. On the other hands, HNF-3β, which is an upstream regulator of the HNF cascade, is believed to play an important role in the expression of essential genes in pancreatic islet functioning. We screened the human HNF-3β gene for mutations in Japanese subjects with early onset NIDDM/MODY of unknown cause and examined the relationship between HNF-3β and the promoter activities of HNF-1α and HNF-4α. We have screened the 3 exons of HNF-3β gene, flanking introns and minimal promoter region for mutations in a group of 70 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause and 20 subjects with IDDM.Eight nucleotide substitutions were noted in HNF-3β gene, of which one resulted in the mutation of a conserved serine residue, Ser109 (AGC) to Asn (AAC) and another resulted in the mutation of alanine residue, Ala328 (GCG) to Val (GTG). The latter mutation was also observed in the sample of her mother. In HNF-1α gene, we recognized one mutation of arginine residue, Arg244 (AGA) to Ser (AGT), located in DNA binding homeodomain. The functional study showed that HNF-3β stimulated both of the HNF-1α and HNF-4α promoter activities and that S109N mutant decreased the HNF-1α promoter activity (p<0.05). These facts indicates HNF is highly involved in the development of early-onset diabetes including type1 diabetes and may be one of causes of early-onset diabetes in Japanese.

Report

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

    (16 results)

All Other

All Publications (16 results)

  • [Publications] Yoshinori Hinokio,: "Oxidative DNA damage in daibetes : Its association with diabetic complications."Diabetologia. 42. 995-998 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Amar Abderrahmani: "Genetic variation in the hepatocyte nuclear factor-3beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians."Diabetes. 49(2). 306-308 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yoshinori Hinokio,: "Beta-cell transcription factors and diabetes : no evidence for diabetes-associated mutations in the hepatocyte nuclear factor-3beta gene (HNF3B) in Japanese patients with maturity-onset diabetes of the young."Diabetes. 49(2). 302-305 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Leslie J.Baier: "Mutations in the genes for HNF-1alpha, -4alpha, -1beta, and -3beta ; the dimerization cofactor of HNF-1 ; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians"Diabtes Care. 23. 302-304 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukio Horikawa: "Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus."Nature Genetics. 26. 163-175 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 檜尾好徳: "症例に学ぶ糖尿病"河盛隆造. 95 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 檜尾好徳: "糖尿病キーワード(改定第2版)"豊田隆謙. 133 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Hinokio, S.Suzuki, M.Hirai, M.Chiba, A.Hirai and T.Toyota.: "Oxidative DNA damage in diabetes : Its association with diabetic complications."Diabetologia. 42. 995-998 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Hinokio, Y.Horikawa, H.Furuta, N.J.Cox, N.Iwasaki, M.Honda, M.Ogata, Y.Iwamoto and G.I.Bell.: "B-cell transcription factors and diabetes. No evidence for diabetes-associated mutations in the hepatocyte nuclear factor-3 beta gene (HNF3B) in Japanese patients with maturity-onset diabetes of the young."Diabetes. 49. 302-305 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] A.Abderrahmani, J.C.Chevre, S.Otabe, M.Chikri, E.H.Hani, M.Vaxillaire, Y.Hinokio, Y.Horikawa, G.I.Bell and P.Froguel.: "Genetic variation in the hepatocyte nuclear factor-3 beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians."Diabetes. 49. 306-308 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] L.J.Baier, P.A.Permana, M.Traurig, A.Dobberfuhl, C.Wiedrich, J.Sutherland, P.Thuillez, G.Luczy-Bachman, M.Hara, Y.Horikawa, Y.Hinokio, R.L.Hanson, C.Bogardus.: "Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, - 4alpha, -1beta, and -3beta ; the dimerization cofactor of HNF-1 ; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians."Diabetes Care. 23. 302-304 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Horikawa, N.Oda, N.J.Cox, N.X.Li, M.Orho-Melander, M.Hara, Y.Hinokio, T.H.Lindner, H.Mashima, P.E.Schwarz, L.del Bosque-Plata, Y.Oda, I.Yoshiuchi, S.Colilla, K.S.Polonsky, S.Wei, P.Concannon, N.Iwasaki, J.Schulze, L.J.Baier, C.Bogardus, L.Groop, E.Boerwinkle, C.L.Hanis and G.I.Bell.: "Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus."Nat Genet. 26. 163-175 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Amar Abderrahmani: "Genetic variation in the hepatocyte nuclear factor-3beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians."Diabetes. 49(2). 306-308 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshinori Hinokio: "Beta-cell transcription factors and diabetes : no evidence for diabetes-associated mutations in the hepatocyte nuclear factor-3beta gene (HNF3B) in Japanese patients with maturity-onset diabetes of the young. "Diabetes. 49(2). 302-305 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Leslie J.Baier,: "Mutations in the genes for HNF-1 alpha, -4 alpha, -1 beta, and -3 beta ; the dimerization cofactor of HNF-1 ; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians"Diabtes Care. 23. 302-304 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshinori Hinokio: "β-cell Transcription Factors and Diabetes"Diabetes. 49. 302-305 (2000)

    • Related Report
      1999 Annual Research Report

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

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