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Elucidation of molecular mechanisms of hereditary neurologic diseases by positional cloning

Research Project

Project/Area Number 04404042
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)
KOIKE Ryoko  Niigata Univ., Medical Hospital/Assistant, 医学部・附属病院, 助手 (60234671)
SOMA Yoshiaki  Niigata Univ., Brain Res.Inst./Lecturer, 脳研究所, 講師 (30163132)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥29,000,000 (Direct Cost: ¥29,000,000)
Fiscal Year 1993: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1992: ¥24,000,000 (Direct Cost: ¥24,000,000)
Keywordspositional cloning / triplet repeat / Machado-Joseph disease / dentatorubral-pallidolyusian atrophy / spinocerebellar degeneration / chromosome 14 / chromosome 12 / chromosome 9 / 副腎白質ジストロフィー / コスミドクローン / X染色体 / 発現遺伝子地図 / ゲノム解析 / hetergernous nuclear RNA / 細胞バンク
Research Abstract

We have applied the strategy of positional cloning as a strategy to identify genes for hereditary neurodegenerative disorder. Among various forms of spinocerebellar degeneration, we have focused out effort on Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and early onset ataxia associated with hypoalbuminemia (EOAHA).
We have initiated systematic linkage analyzes of MJD using microsatellite polymorphisms. After checking 90 microsatellite markers, we have found that the MJD is tightly linked to D14S55 and D14S48 with a maximum lod score of 9.719. To further narrow down the candidate region, further detailed linkage as well as linkage disequilibrium analysis will be required.
With the background that unstable expansion of trinucleotide repeat is a common mechanism for neurodegenerative disorder, we have hypothesized that DRPLA is caused by the similar mechanism, because a prominent anticipation (accelerated ages of onset in successive generations), a characteristic feature for triplet repeat diseases, is observed in DRPLA as well. By searching for genes with trinucleotide repeat, we have discovered that DRPLA is caused by unstable expansion of trinucleotide repeat in the gene located on chromosome 12. Close correlation between ages of onset and the degree of expanded trinucleotide repeat suggests that the expansion of the CAG repeat is intimately involved in the pathogenesis of DRPLA.
With detailed linkage analysis we have doscpvered that the gene is lcoated on chromosome 9. Although the gene for EOAHA is located near the locus for Friedreich's ataxia, observation of multiple recombination events involving the Friedreich's locus
suggests that EOAHA is a distinct disease from a genetic point of view.

Report

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

    (63 results)

All Other

All Publications (63 results)

  • [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
      1993 Final Research Report Summary
  • [Publications] Takano,H.,et al.: "Chromosomal localization of the ε1,ε3 and ζ1 subunit genes of the human NMDA receptor channel." Biochem.Biophys.Res.Commun.197. 922-926 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imai,K.,et al.: "A novel transcript from a pseudogene for human glucocerebrosidase in nonGaucher disease cells." Gene. 136. 365-368 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Honke,K.,et al.: "An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A." Hum.Genet.92. 451-456 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko,K.,et al.: "Hypertrophic cardiomyopathy and increased number of CAG repeats in the androgen receptor gene." Am.Heart J.126. 248-249 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tanaka,H.,et al.: "Absence of linkage disequilibrium at amyloid precursor protein gene locus in Japanese familial Alzheimer's disease with ^<717>Val→Ile mutation." Neurosci.Lett.162. 63-66 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mullan,M.,et al.: "Clinical comparison of Alzheimer's disease in pedigrees with the codon ^<717>Val→Ile mutation in the amyloid precursor protein gene." Neurobiol.Aging. 14. 407-419 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tanno,Y.,et al.: "Uniform tissue distribution of tRNA^<Lys> mutation in mitochondrial DNA in MERRF patients." Neurology. 43. 1198-1200 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kobayashi,H.,et al.: "Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system." Mol.Brain Res.19. 188-194 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko,K.,et al.: "Isolation of 353 NotI linking clones and 62 DNA markers (DXS607-DXS668) from human chromosome Xq24-qter." Cytogenet.Cell Genet.64. 5-8 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Takiyama,Y.,et al.: "The gene for Machado-Joseph disease maps to human chromosome 14q." Nature Genet.4. 300-304 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Igarashi,S.,et al.: "Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy." Neurology. 42. 2300-2302 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tomita,Y.,et al.: "Interferon γ but not tumor necrosis factor α decreases susceptibility of human renal cell cancer cell lines to lymphokine-activated killer cells." Cancer Immunol.Immunother.35. 381-387 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko,K.,et al.: "Genomic organization of a cDNA(QM)demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells and its location to Xq28." Hum.Mol.Genet.1. 529-533 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tsuji,S.,et al.: "Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease." EMBO J.11. 4843-4850 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Uyama,E.,et al.: "Hydrocephalus,corneal opacities,deafness,valvular heart disease,deformed toes and leptomeningeal fibrous thickening in adult siblings:" Acta Neurol.Scand.86. 407-420 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imagawa,M.,et al.: "Coenzyme Q_<10>,iron,and vitamin B_6 therapy in genetically-confirmed Alzheimer's disease." Lancet. 340. 671-671 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] McInnes,B.,et al.: "An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds." J.Clin.Invest.90. 306-314 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sidransky,E.,et al.: "Gaucher patients with oculomotor abnormalities do not have a unique genotype." Clin.Genet.41. 1-5 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sidransky,E.,et al.: "DNA mutation analysis of Gaucher patients." Am.J.Med.Genet.42. 331-336 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Wakamatsu,N.,et al.: "A novel exon mutation in the human β-hexosaminidase β subunit gene affects 3' splice site selection." J.Biol.Chem.267. 2406-2413 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tsuji,S.et al.: "Hereditary Progressive Dystonia with Marked Diurnal Fluctuation (Segawa,M.ed.)" The Parthenon Publishing Group,Lancs.U.K., 8 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Koide, R., et al.: "Unstable expansion of CAG repeat in hereditary dentatorubral-palidoluysian atrophy (DRPLA)." Nature Genet. 6(1). 9-13 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Takano, H., et al.: "Chromosomal localization of the epsilon1, epsilon3 and zeta1 subunit genes of the human NMDA receptor channel." Biochem.Biophys.Res.Commun.197(2). 922-926 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imai, K., et al.: "a novel transcript from a pseudogene for human glucocerebrosidase in non-Gaucher disease cells." Gene. 136. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Honke, K., et al.: "An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A." Hum.Genet.92. 451-456 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko, K., et al.: "Hypertrophic cardiomyopathy and increased number of CAG repeats in the androgen receptor gene." Am.Heart J.126. 248-249 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tanaka, H., et al.: "Absence of linkage disequilibrium at amyloid precursor protein gene locus in Japanese familial Alzheimer's disease with ^<717>Val->Ile mutation." Neurosci. Lett.162. 63-66 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mullan, M., et al.: "Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val->Ile mutation in the amyloid precursor protein gene." Neurobiol.Aging. 14(5). 407-419 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tanno, Y., et al.: "Uniform tissue distribution of tRNA^<Lys> mutation in mitochondrial DNA in MERRF patients." Neurology. 43(6). 1198-1200 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kobayashi, H., et al.: "Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system." Mol.Brain Res.19(3). 188-194 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko, K., et al.: "Isolation of 353 NotI linking clones and 62 DNA markers (DXS607-DXS668) from human chromosome Xq24-qter." Cytogenet. Cell Genet.64(1). 5-8 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Takiyama, Y., et al.: "The gene for Machado-Joseph disease maps to human chromosome 14q." Nature Genet.4(4). 300-304 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tsuji, S., et al.: "Linkage analysis of hereditary progressive dystonia to the tyrosine hydroxylase gene locus." In : Hereditary Progressive Dystonia with Marked Diurnal Fluctuation, edited by Segawa, M., The Parthenon Publishing Group, Lancs, U.K.107-114 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Igarashi, S., et al.: "Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy." Neurology. 42(12). 2300-2302 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tomita, Y., et al: "Interfeon gamma but not tumor necrosis factor alpha decreases susceptibility of human renal cell cancer cell lines to lymphokine-activated killer cells." Cancer Immunol. Immunother. 35. 381-387 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kaneko, K., et al: "Genomic organization of a cDNA (QM) demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells and its location to Xq28." Hum.Mol.Genet.1(7). 529-533 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tsuji, S., et al.: "Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease." EMBO J.11(13). 4843-4850 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Uyama, E., et al.: "Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings : a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells." Acta.Neurol.Scand.86. 407-420 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imagawa, M., et al.: "Coenzyme Q_<10>, iron, and vitamin B_6 therapy in genetically-confirmed Alzheimer's disease." Lancet. 340(8820). 671 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] McInnes, B., et al.: "An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds." J.Clin.Invest. 90. 306-314 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sidransky, E., et al.: "Gaucher patients with oculomotor abnormalities do not have a unique genotype." Clin.Genet.41(1). 1-5 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sidransky, E., et al.: "DNA mutation analysis of Gaucher patients." Am.J.Med.Genet.42. 331-336 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Wakamatsu, N., et al.: "A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection." J.Biol.Chem.267(4). 2406-2413 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 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)

    • Related Report
      1993 Annual Research Report
  • [Publications] Takano,H.,et al.: "Chromosomal localization of the ε1,ε3 and ζ1 subunit genes of the human NMDA receptor channel." Biochem.Biophys.Res.Commun.197. 922-926 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Imai,K.,et al.: "A novel transcript from a pseudogene for human glucocerebrosidase in non-Gaucher disease cells." Gene. 136. 365-368 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Honke,K.,et al.: "An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A." Hum.Genet.92. 451-456 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kaneko,K.,et al.: "Hypertrophic cardiomyopathy and increased number of CAG repeats in the androgen receptor gene." Am.Heart J.126. 248-249 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tanaka,H.,et al.: "Absence of linkage disequilibrium at amyloid precursor protein gene locus in Japanese familial Alzheimer's disease with ^<717>Val→Ile mutation." Neurosci.Lett.162. 63-66 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Mullan,M.,et al.: "Clinical comparison of Alzheimer's disease in pedigrees with the codon 717Val→Ile mutation in the amyloid precursor protein gene." Neurobiol.Aging. 14. 407-419 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tanno,Y.,et al.: "Uniform tissue distribution of tRNA^<Lys> mutation in mitochondrial DNA in MERRF patients." Neurology. 43. 1198-1200 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kobayashi,H.,et al.: "Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system." Mol.Brain Res.19. 188-194 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kaneko,K.,et al.: "Isolation of 353 NotI linking clones and 62 DNA markers(DXS607-DXS668)from human chromosome Xq24-qter." Cytogenet.Cell Genet.64. 5-8 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Takiyama,Y.,et al.: "The gene for Machado-Joseph disease maps to human chromosome 14q." Nature Genet.4. 300-304 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Wakawatsu,N.,et al.: "A novel exon mutation in the human β-hexosaminidase β subunit gene affects 3' splice site selection." J.biol.Chem.267. 2406-2413 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sidransky,e.,et al.: "DNA mutation analysis of Gaucher patients." Am.J.Med.Genet.42. 331-336 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sidransky,e.,et al.: "Gaucher patients with oculomotor abnormalities do not have a unique genotype." Clin.Genet.41. 1-5 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] McInnes,B.,et al.: "An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds." J.Clin.Invest.90. 306-314 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Imagawa,B.,et al.: "Coenzyme Q10-iron-vitamin B6 therapy prevents the progression of dementia in genetically-confirmed Alzheimer's disease." Lancet. 340. 671-671 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Uyama,E.,et al.: "Hydrocephalus,corneal opacities,deafness,valvular heart diseade,deformed toes and leptomeningeal fibrous thickening in abult siblings:" Acta Neurol.Scand.86. 407-420 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tsuji,S.,et al.: "Molecular cloning of human growth inhibitory factor cDNA and its dowm-regulation in Alzheimer's disease." EMBO J.11. 4843-4850 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kaneko,K.,et al.: "Genomic organization of a cDNA(QM)demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells and its location to Xp28." Hum.Mol.Genet.1. 529-533 (1992)

    • Related Report
      1992 Annual Research Report

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

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