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Elucidation of molecular mechanisms of spinocerebellar degeneration through positional cloning of causative genes and development of the animal models.

Research Project

Project/Area Number 06404030
Research Category

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

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionNiigata University

Principal Investigator

TSUJI Shoji  Niigata Univ, Brain Res Inst/Professor, 脳研究所, 教授 (70150612)

Co-Investigator(Kenkyū-buntansha) TANAKA Hajime  Niigata Univ, Brain Res Inst/Assistant, 脳研究所, 助手 (20251845)
HOZUMI Isao  Niigata Univ, Med Hospital/Assistant, 医学部付属病院, 助手 (20242430)
INUZUKA Takashi  Niigata Univ, Med Hospital/Lecturer, 医学部付属病院, 講師 (50184734)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥36,100,000 (Direct Cost: ¥36,100,000)
Fiscal Year 1995: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1994: ¥31,200,000 (Direct Cost: ¥31,200,000)
KeywordsSpinocerebellar degeneration / Triplet repeat / CAG repeat / Transgenic mouse / Embryonic stem cell / Somatic mosaicism / Genomic instability / Animal models / 遺伝性疾患 / 神経変性疾患 / CAG repeat / triplet repeat / gene targetting
Research Abstract

To elucidate molecular mechanisms of neuronal degeneration in hereditary spinocerebellar ataxia, and to develop therapeutic measures for these diseases, we have attempted to create animal models for dentatorubral-pallidoluysian atrophy (DRPLA), a form of hereditary spinocerebellar degenerations . As the first step, we have isolated and determined the detailed structures of full length human and mouse cDNA clones for DRPLA .Furthermore, we have also isolated human and mouse genomic DNA for DRPLA . We have revealed that the DRPLA gene is widely expressed not only in the central nervous system but also in the somatic organs . We have found that there is a considerable somatic mosaicism of the expanded CAG repeats in the central nervous system of DRPLA patients, suggesting the somatic instability of the expanded CAG repeats . To create animal models, we have undertaken two strategies . As one strategy, we have cloned a genomic clone from a DRPLA patient with the longest (78 repeat) CAG repeat, which was inserted into embryonic stem cells (ES cells) with a selectable marker . ES cells containing single copy of mutant DRPLA gene were selected and chimeric mice was obtained . Germline transmission is being attempted now . As another strategy, we have created mutant human DRPLA cDNA carrying the expanded CAG repeat . Transgenic mouse carrying multiple copies of the mutant DRPLA cDNA were made, and the phenotype is being investigated . These two lines of animal models should be highly useful for the future study of the molecular mechanisms of DRPLA,and to develop therapeutic measure for DRPLA .

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (46 results)

All Other

All Publications (46 results)

  • [Publications] Takiyama,Y.,et al.: "Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease." Hum.Mol.Genet.4. 1137-1146 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Onodera,O.,et al.: "Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS." Am.J.Hum.Genet.57. 1050-1060 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Okuizumi,K.,et al.: "Genetic association of the very low density lipoprotein(VLDL) receptor gene with sporadic Alzheimer's disease." Nature Genet.11. 207-209 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Sanpei,K.,et al.: "Direct detection of expanded (CAG/CTG) repeats in the myotonin-protein kinase genes of myotonic dystrophy patients using a high-stringency hybridization method." Biochem.Biophys.Res.Commun.212. 341-346 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy closely related to unstable expansions of trinucleotide (CAG) repeat." Ann.Neurol.37. 769-775 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA." Clin.Neurosci.3. 23-27 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA): Close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation." Seminars in Cell Biology. 6. 37-44 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tanaka,H.,et al.: "The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q." Ann.Neurol.37. 405-408 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Burke,J.R.,et al.: "Dentatorubral-pallidoluysian atrophy and Haw River syndrome." Lancet. 344. 1711-1712 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ichinose,H.,et al.: "Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene." Nature Genet.8. 236-242 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Naruse,S.,et al.: "Structures of the human and mouse growth inhibitory factor-encoding genes." Gene. 144. 283-287 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Sequeiros,J.,et al.: "Genetic linkage studies of Machado-Joseph disease with chromosome 14q STRPs in 16 Portuguese-Azorean kindreds." Genomics. 21. 645-648 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Okuizumi,K.,et al.: "ApoE-ε4 and early-onset Alzheimer's." Nature Genet.7. 10-11 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakano,R,et al.: "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis." Biochem.Biophys.Res.Commun.200. 695-703 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Koide,R.,et al.: "Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA)." Nature Genet.6. 9-13 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takiyama, Y., et al.: "Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease." Hum.Mol.Genet.4. 1137-1146 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Onodera, O., et al.: "Moleuclar cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS." Am.J.Hum.Genet.57. 1050-1060 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Okuizumi, K., et al.: "Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimers disease." Nature Genet.11. 207-209 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Sanpei, K., et al.: "Direct detection of expanded (CAG/CTG) repeats in the myotonin-protein kinase genes of myotonic dystrophy patients using a high-strigency hybridization method." Biochem.Biophys.Res.Commun.212. 341-346 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi, T., et al.: "Dentatorubral-pallidoluysian atrophy closely related to unstable expansions of trinucleotide (CAG) repeat." Ann.Neurol.37. 769-775 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi, T., et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA." Clin.Neurosci.3. 23-27 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ikeuchi, T., et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA) : close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation." Seminars in Cell Biology. 6. 37-44 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tanaka, H., et al.: "The gene for hereditary progressive dystonia with marked diumal fluctuation maps to chromosome 14q." Ann.Neurol.37. 405-408 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Burke, J.R., et al.: "Dentatorubral-pallidoluysian atrophy and Haw River syndrome." Lancet. 344. 1711-1712 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ichinose, H., et al.: "Hereditary progressive dystonia with marked diumal fluctuation caused by mutations in the GTP cyclohydrolase I gene." Nature Genet.8. 236-242 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Naruse, S., et al.: "Structures of the human and mouse growth inhibitory factor-encoding genes." Gene. 144. 283-287 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Sequeiros, J., et al.: "Genetic linkage studies of Machado-Joseph disease with chromosome 14q STRPs in 16 Portuguese-Azorean kindreds." Genomics. 21. 645-648 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Okuizumi, K., et al.: "ApoE-epsilon 4 and early-onset Alzheimer's." Nature Genet.7. 10-11 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakano, R., et al.: "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis." Biochem.Biophys.Res.Commun.200. 695-703 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Koide, R., et al.: "Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA)." Nature Genet.9. 9-13 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takiyama,Y.,et al.: "Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease." Hum.Mol.Genet.4. 1137-1146 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Onodera,O.,et al.: "Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS." Am.J.Hum.Genet.57. 1050-1060 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Okuizumi,K.,et al.: "Genetic association of the very low density lipoprotein(VLDL)receptor gene with sporadic Alzheimer's disease." Nature Genet.11. 207-209 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Sanpei,K.,et al.: "Direct detection of expanded(CAG/CTG)repeats in the myotonin-protein kinase genes of myotonic dystrophy patients using a high-stringency hybridization method." Biochem.Biophys.Res.Commun.212. 341-346 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy closely related to unstable expansions of trinucleotide(CAG)repeat." Ann.Neurol.37. 769-755 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy(DRPLA).Molecular basis for wide clinical features of DRPLA." Clin.Neurosci.3. 23-27 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ikeuchi,T.,et al.: "Dentatorubral-pallidoluysian atrophy(DRPLA):Close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation." Seminars in Cell Biology. 6. 37-44 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tanaka,H.,et al.: "The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14g." Ann.Neurol.37. 405-408 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Burke,J.R.,et al.: "Dentatorubral-pallidoluysian atrophy and Haw River syndrome." Lancet. 344. 1711-1712 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ichinose,H.,et al.: "Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene." Nature Genet.8. 236-242 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Naruse,S.,et al.: "Structures of the human and mouse growth inhibitory factorencoding genes." Gene. 144. 283-287 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fujigasaki,H.,et al.: "Mutational analysis of the amyloid precursor protein gene in Japanese familial Alzheimer's disease kindreds." Hum.Genet.93. 460-462 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Sequeiros,J.,et al.: "Genetic linkage studies of Machado-Joseph disease with chromosome 14q STRPs in 16 Portuguese-Azorean kindreds." Genomics. 21. 645-648 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Okuizumi,K.,et al.: "ApoE-ε4 and early-onset Alzheimer's disease." Nature Genet.7. 10-11 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nakano,R.,et al.: "A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis." Biochem.Biophys.Res.Commun.200. 695-703 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Koide,R.,et al.: "Unstable expansion of CAG repeat in hereditary dentatorubralpallidoluysian atrophy(DRPLA)." Nature Genet.6. 9-13 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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