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レーザーマイクロダイセクションを用いたCAGリピートの不安定化機構の研究

Research Project

Project/Area Number 11470148
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionJichi Medical School

Principal Investigator

TAKIYAMA Yoshihisa  Jichi Medical School, Dept. Neurology, Lecturer, 医学部, 講師 (00245052)

Co-Investigator(Kenkyū-buntansha) NAMEKAWA Michito  Jichi Medical School, Dept. Neurology, Assistant Professor, 医学部, 助手
SHIMAZAKI Haruo  Jichi Medical School, Dept. Neurology, Assistant Professor, 医学部, 助手 (30316517)
NISHIZAWA Masatoyo  International University of Health and Welfare, Dept. Neurology, Professor, 教授 (80198457)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2000: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1999: ¥9,900,000 (Direct Cost: ¥9,900,000)
KeywordsLaser microdissection / CAG repeats / Meiotic instability / Mitotic instability / MJD / SCA6 / Umbilical cord blood / Huntington disease
Research Abstract

We investigated the molecular mechanism on the meiotic and mitotic instability of CAG repeats causing neurodegenerative disorders such as Huntington disease (HD) and hereditary ataxias.
First, employing a laser-captured microdissection (LCM), we investigated the meiotic instability of CAG repeats in the germ-line cells in the Huntington disease (HD) replacement mouse. LCM enables the isolation of single lineage testicular cells for subsequent molecular analysis. We found that CAG repeats in the spermatid are significantly smaller than the spermatocyte in the mouse homozygous for the expanded allele (Mann-Whitney U test, P<0.05). With regard to the mouse examined, the CAG repeats tended to contract with the cell differentiation.
Sccond, we investigated the mitotic instability of CAG repeats in the variable brain cell lineage in two patients with Machado-Joseph disease (MJD) using LCM.We found that CAG repeat size in the cells of cerebellar cortex (molecular, Purkinje, and granular cell la … More yers) is significantly smaller than that in the cells of cerebellar white matter (Mann-Whitney U test, P<0.05). There was no significant differences in the CAG repeat size among the cells of the cerebellar cortex.
Third, although the intergenerational stability of the CAG repeat number has been considered to be a specific molecular feature of SCA6 compared with other CAG repeat diseases, we showed meiotic instability of the CAG repeats in the SCA6/CACNL1A gene in two Japanese SCA6 families, including de novo expansion. In one family, the CAG _<20> allele expanded to the CAG_<26> one during paternal transmission, and in the other family, the CAG_<19> allele expanded to the CAG_<20> one during maternal transmission. This is the first case of haplotype analysis-proven de novo expansion in SCA6, confirming the derivation of an expanded allele from one normal allele.
Finally, we examined whether the postnatal expansion of the CAG repeats in the blood cells for 'CAG repeat diseases' occurs. We analyzed the CAG repeats in the umbilical cord blood (UCB) and peripheral blood (PB) cells with HD and MJD in adulthood. We found that somatic mosaicism in the blood cells of HD and MJD significantly increases over time (Mann-Whitney U test, P<0.005), indicating that somatic instability is continuous throughout the life of patients. This is the first report on the somatic instability of CAG repeats in the blood cells of 'CAG repeat diseases'. Less

Report

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

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Yamashita I: "A novel locus for dominant cerebellar ataxia (SCA14) maps to a10,2-CM interval flanked by D19S206 and D19S605 on chromosome19q13,4-qter."Ann Neurol. 48. 156-163 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimohata T: "Expanded polyslutamine stretches interact with TAFII130, interfering with CRER-dependent transcription."Nature Genet. 26. 29-36 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yabe I: "Predisposing chromosome of spinocerebellar ataxia type 6 (SCA6) in Japanese."J Med Genet. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhou YX: "Spinocerebellar ataxia type1 in Chian : molecular analysis and genotype-phenotype correlation in five families."Arch Neurol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimazaki H: "Meiotic instability of the CAG repeats in the SCA6/CACNALA gene in two Japanese SCA6 families."J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Namekawa M: "A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene ; a clinical and genetic study."J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 法化図陽一: "Spino cerebellar ataxia type6(SCA6)の-家系:その臨床徴候を主体に."臨床神経. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 滝山嘉久: "遺伝性神経筋疾患の最新情報:Machado-Joseph病"内科. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takiyama, Y.et al.: "Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA) : the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases."Hum.Mol.Genet.. 8. 453-457 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takiyama, Y.et al.: "An unusual case of facial diplegia."Muscle & Nerve. 22. 778-779 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawakami, T.et al.: "A case of McLeod syndrome with unusually severe myopathy."J.Neurol.Sci. 166. 36-39 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sawada, M.et al.: "Vocal cord paralysis in spinal and bulbar muscular atrophy."Igaku no Ayumi. 191 (in Japanese). 833-835 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawakami, T.et al.: "An unusual case of epilepsy exhibiting gelastic seizure, simple visual hallucination, and transient swelling of the left parieto-occipital region."Clin.Neurol. 40 (in Japanese). 24-28 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita, I.et al.: "A novel locus for dominant cerebellar ataxia (SCA 14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter."Ann Neurol. 48. 156-163 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hokezu, Y.et al.: "A clinical features of a famaily with spinocerebellar ataxia type 6 (SCA6)."Oita Kenritsu Byoin Igaku Zasshi. 29 (in Japanese). 113-117 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimohata, T.et al.: "Expanded polyglutamine stretches interact with TAF_<II>130, interfering with CREB-dependent transcription."Nature Genet. 26. 29-36 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yabe, I.et al.: "Predisposing chromosome of spinocerebellar ataxia type 6 (SCA6) in Japanese."J Med Genet. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhou, Y.-X.et al.: "Spinocerebellar ataxia type 1 in China : molecular analysis and genotype-phenotype correlation in five families."Arch Neurol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hokezu, Y.et al.: "A familial case of spinocerebellar ataxia type 8 (SCA8) : its clinical findings and an issue about the genetic basis."Clin. Neurol.. (in Japanese, in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimazaki, H.et al.: "Meiotic instability of the CAG repeats in the SCA6/CACNA1A gene in two Japanese SCA6 families"J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Namekawa, M.et al.: "A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene : a clinical and genetic study."J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takiyama, Y.et al.: "Late cortical cerebellar atrophy"Medical Syndromes of Neurological Diseases II, Nippon Rinsho, Osaka. (in Japanese). 247-250 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takiyama, Y.: "Machado-Joseph disease."Naika. (in Japanese, in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita I: "A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter."Ann Neurol. 48・2. 156-163 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimohata T: "Expanded polyglutamine stretches interact with TAF_<II> 130, interfering with CREB-dependent transcription."Nature Genet. 26・1. 29-36 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yabe I: "Predisposing chromosome of spinocerebellar ataxia type 6 (SCA6) in Japanese."J Med Genet. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhou YX: "Spinocerebellar ataxia type 1 in China : molecular analysis and genotype-phenotype correlation in five families."Arch Neurol. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimazaki H: "Meiotic instability of the CAG repeats in the SCA6/CACNAIA gene in two Japanese SCA6 families."J Neurol Sci. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Namekawa M: "A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene : a clinical and genetic study."J Neurol Sci. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 法化図陽一: "Spinocerebellar ataxia type6(SCA6)の一家系:その臨床徴候を主体に."臨床神経. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] 滝山嘉久: "遺伝性神経筋疾患の最新情報:Machado-Joseph病"内科. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Takiyama Y: "Single Sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysion atrophy(DRPLA) : the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases"Hum Mol Genet. 8. 453-457 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takiyama Y: "An unusual case of facial diplegia"Muscle & Nerve. 22. 778-779 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawakami T: "A case of McLeod Syndrome with unusually severe myopathy"J Neurol Sci. 166. 36-39 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 澤田幹雄: "運動ニューロン疾患、球脊髄性筋萎縮症と声帯麻痺"医学のあゆみ. 191. 833-835 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 滝山嘉久: "神経症候群11、晩発性皮質小脳萎縮症"日本臨床社. 4 (1999)

    • Related Report
      1999 Annual Research Report

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

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