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Identification of the gene for Huntington's disease by reverse genetus.

Research Project

Project/Area Number 04404041
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionThe University of Tokyo

Principal Investigator

KANAZAWA Ichiro  Faculty of Medicine, The University of Tokyo, Professor, 医学部(医), 教授 (30110498)

Co-Investigator(Kenkyū-buntansha) 中瀬 浩史  東京大学, 医部学(医), 講師 (80155738)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥30,500,000 (Direct Cost: ¥30,500,000)
Fiscal Year 1994: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1993: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1992: ¥19,500,000 (Direct Cost: ¥19,500,000)
KeywordsHuntington disease / Genetic linkage / chromosome 4 / YAC clone / IT15 gene / CAG repeat / huntingtin / DNAマーカー / 連鎖不平衡
Research Abstract

Huntington's disease is an autosomal dominant neurodegenerative disorder. Its causal gene was located at the short arm of chromosome 4.Immediately before the start of this project, the gene for Huntington'd siease was identified by Gusella in Boston. Therefore, in the middle of the term, the aims of this study was shifted to the molecular biological analysis of the CAG repeat of the gene.
(1) In order to identify the causal gene for Huntington's disease, we constructed the yeast artificial chromosome (YAC) and using this several hitherto unknown genes were cloned from the Huntington's disease region. However, those are not related to Huntington's disease, unfortunately.
(2) After the identification of IT15 gene as the gene for Huntington's disease, CAG repeat number was extensively investigated. The distribution of the number of CAG repeat in Japanese normal people and Huntington's disease patient were exactly the same as those of the Western countries. When the CAG repeat number of Hunt … More ington's disease patients were plotted against the age at onset, there was clear inverse correlation ; longer the earlier onset and shorter the later onset. In cases of juvenile onset of the disease ; younger than 20 years old, the gene for the disease comes from the father whose sperms should have various numbers of CAG repeat. Moreover, the frequency of the individual having intermediate number of CAG repeat was obviously high in Western countries in which the frequency of the disease is also high, and vice versa.
(3) There is a polymorphism in the CCG repeat located just after the CAG repeat in IT15 gene. Using this as a marker, we performed an haplotype analysis. We found that the the origin of Japanese Huntington's disease should be not Western countries but somewhere in Asia or Japan.
(4) The CAG repeat is located just in the coding region of IT15 gene. Therefore, the protein having abnormally long glutamine stretch should be expressed in brain. We raised the specific antibody against the IT15 gene product (huntingtin) and performed Western analysis. We found the actual expression of huntingtin in every tissue in the central nervous system. Less

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Hadano S., Ishida Y., Bates GP., Nagayama T., Kanazawa I., Lehrach H.and Ikeda J.: "Generation of High-Density DNA Markers from Yeast Artificial Chromosome DNA by Single Unique Primer-Polymerase Chain Reaction." GATA. 10. 105-108 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Watanabe M., Kondo I., Nissato S., wakisaka A., Toda T., Ikeda J., Wasmuth JJ., Gusella JF.and Kanazawa I.: "A Linkage Study with DNA Markers (D4S95,D4S115,and D4S111) in Japanese Huntington Disease Families." Jpn J Human Genet. 38. 193-201 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Masuda N., Goto J., Murayama N., Watanabe M., Kondo I.and Kanazawa I.: "Analysis of triplet repeats in the huntingtin gene in Japanese families affected with Huntington's disease." J Med Genet. 32. 701-705 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Squitieri F., Andrew SE., Goldberg YP., Kremer B., Spence N., Nichol K., Theilman J.,et.al.: "DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence." Human Molecular Genetics. 3. 2103-2114 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Almqvist E., Spence N., Nichol K., Andrew SE., Vesa J., Peltonen L., Anvret M., Goto J., Kanazawa I.,et.al.: "Ancestral difference in the distribution of the Δ2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes : insights into the genetic evolution of Huntington disease." Human Molecular Genetics.4. 207-214 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ide K., Nukina N., Masuda N., Goto J.and Kanazawa I.: "Abnormal Gene Product Identified in Huntington's Disease Lymphocytes and Brain." Biochemical and Biophysical Research Communication. 209. 1119-1125 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hadano S., Ishida Y., Bates GP., Nagayama T., Kanazawa I., Lehrach H.and Ikeda J.: "Generation of High-Density DNA Markers from Yeast Artificial Chromosome DNA by Single Unique Primer-Polymerase Chain Reaction." GATA. 10(5). 105-108 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Watanabe M., Kondo I., Nissato S., Wakisaka A., Toda T., Ikeda J., Wasmuth JJ., Gusella JF.and Kanazawa I.: "A Linkage Study with DNA Markers (D4S95, D4S115, and D4S111) in Japanese Huntington Disease Families." Jpn J Human Genet. 38. 193-201 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Masuda N., Goto J., Murayama N., Watanabe M., Kondo I.and Kanazawa I.: "Analysis of triplet repeats in the huntingtin gene in Japanese families affected with Huntington's disease." J Med Genet.32. 701-705 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Squitieri F., Andrew SE., Goldberg YP., Kremer B., Spence N., Zeisler J., Nichol K., Theilman J., Greenberg J., Goto J., Kanazawa I., Vesa J., Peltonen L., Almqvist E., Anvret M., Telenius H., Lin B., Napolitano G., Morgan K.and Hayden MR.: "DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence." Human Molecular Genetics. 3(12). 2103-2114 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Almqvist E., Spence N., Nichol K., Andrew SE., Vesa J., Peltonen L., Anvret M., Goto J., Kanazawa I., Goldberg YP.and Hayden MR.: "Ancestral difference in the distribution of the DELTA2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes : insights into the genetic evolution of Huntington disease." Human Molecular Genetics. 4(2). 207-214 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ide K., Nukina N., Masuda N., Goto J.and Kanazawa I.: "Abnormal Gene Product Identified in Huntington's Disease Lymphocytes and Brain." Biochemical and Biophysical Research Communication. 209(3). 1119-1125 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nagafuchi S.,Yanagisawa H.,Sato K.,Shirayama T.,Ohsaki E.,: "Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p." Nature Genetics. 6. 14-18 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kanazawa I: "Diagnosis and genetic counseling for Huntington's disease." Intractable Neurological Disorders,Human Genome Research and Society;Proceeding of the Third International Bioethics Seminar in Fukui. 75-76 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 後藤順,金澤一郎: "ハンチントン病/Huntington's disease" 実験医学. 12(増刊). 720-724 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Toda T,Ikegawa S,Okui K,Kondo E,Saito K,Fukuyama Y,: "Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy:Evidence for strong linkage disequilibrium." Am J Hum Genet. 55. 946-950 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Squitieri F,Andrew SE,Goodberg YP,Kremer B,: "DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence." Human Molecular Genetics. 3. 2103-2114 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hadano S.,Ishida Y.,Bates GP.,Nagayama T.,Kanazawa I.,: "Generation of high-density DNA markers from yeast artificial chromosome DNA by single unique primer-polymerase chain reaction." GATA. 10. 105-108 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] 金澤一郎: "分子遺伝学的異常による大脳基底核疾患" 脳と神経. 45. 129-132 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kanazawa I,Murata M,and Kimura M.: "Roles of dopamine and its receptors in generation of choreic movements." Advances in Neurology. 60. 107-112 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Watanabe M,Kondo I,Kanazawa I.: "A linkage study with DNA markers(D4S95,D4S115 and D4S111)in Japanese Huntington disease families." Japanese Journal of Human Genetics. 38. 193-201 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 桜井靖久・金澤一郎: "ハンチントン病と痴呆" 老年精神医学雑誌. 4. 1118-1123 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Toda T,Segawa M,Kanazawa I.: "Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9g31-33." Nature Genetics. 5. 283-286 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nagafuchi S,Kanazawa I: "Dentatorubropallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p." Nature Genetics. 6. 14-18 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Watanabe M,Kondo INissato s,Wakisaka Ikeda J,Kabazawa I: "Studies on 4p16.3 DNA marhers (D4S95,D4S115&D4Slll)in Japanese Huntington's disease families." Jap.J.Hum.Gent.in press.

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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