1996 Fiscal Year Annual Research Report

Machado-Joseph病原因遺伝子(MJD1)の不安定性について

Research Project

Project/Area Number	08670722
Research Institution	Jichi Medical University
Principal Investigator	滝山嘉久自治医科大学, 医学部, 助手 (00245052)
Co-Investigator(Kenkyū-buntansha)	西澤正豊自治医科大学, 医学部, 助教授 (80198457)
Keywords	Machado-Joseph病 / MJD1遺伝子 / instability / single sperm
Research Abstract	我々は、これまで、Machado-Joseph病(MJD)家系の臨床遺伝学的な観察により、(1)MJDの原因遺伝子(MJD1)内の正常アリル(NA)のCGG/GGG多型が、増大アリル(EA)のCAGリピートの不安定性に大きく影響を与えること(inter-allelic interaction)と、(2)病気が父親由来の時には、子供の世代での発症者の比率が高いこと(meiotic drive)を報告してきた。今回、我々はこれらの現象をspermレベルで、より直接的に証明することを目的として、MJD患者6名の計1036個のsingle spermのCAGリピート数の解析を行った。その結果、(1)EA-CGG/NA-GGG患者のspermは、EA-CGG/NA-CGG患者のspermよりもCAGリピート数の変化のvariance有意に高かった。(F-test、P<0.001)。(2)EAとNAの分離比は、629対407であり、Mendelの遺伝の法則から考えられる1対1の分離比から有意にずれていた(χ^2=47.57、P<0.0001)。(3)EAのmutation rateは88-99%で、白血球から抽出したDNAに比べて32%がexpansionを呈し、60%がcontractionを呈していた。NAのmutataion rateは0-4%であり、NAのうち最も短い14リピートは安定であった。以上、我々が臨床遺伝学的な観察により、報告してきたinter-allelic interactionとmeiotic driveの現象をspermレベルで、より直接的に証明することができた(現在投稿中)。MJD1の不安定性は、Huntington病、Kennedy病、Myotonic dystrophyなど他のトリプレット・リピート病と共通点や相違点があり、今後、トリプレット・リピート病原因遺伝子のMeioticおよびMeitoticな不安定性の機序につき、更なる検討を行う予定である。

Research Products
(8 results)

All Other

All Publications (8 results)

[Publications] Takiyama Y: "Machado-Joseph diseas : cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expanded allele (56 CAG repeat units) of the MJD1 gene." Neurology. (in press).
[Publications] Zhou YX: "Machado-Joseph disease in four Chinese pedigrees : molecular analysis of 15 patients including 2 juvenile cases and clinical correlations." Neurology. 48. 480-482 (1997)
[Publications] Igarashi S: "Intergenerational instability of the CAG repeat of the gene for Machado-Joseph diseas (MJD1) is affected by the genotype of the normal chromosome : implication for the molecular mechanisms of the instability of the CAG repeat" Hum Mol Genet. 5. 923-932 (1996)
[Publications] Endo K: "Strong Linkage disequilibrium and haplotype analysis in Japanese pedigrees with Machado-Joseph disease (MJD)." Am J Med Genet. (in press).
[Publications] Ikeuchi T: "Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD): mutant allele is preferentially transmitted in male meiosis." Am J Hum Genet. 58. 730-733 (1996)
[Publications] Ishikawa K: "Pure cerebellar ataxia phenotype in Machado-Joseph disease." Neurology. 46. 1776-1777 (1996)
[Publications] Sanpei K: "Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique,DIRECT." Nature Genet. 14. 277-284 (1996)
[Publications] 滝山嘉久: "キーワード1997-98´神経変性疾患(分担執筆)Machado-Joseph病" 先端医学社水野美邦編(印刷中),

1996 Fiscal Year Annual Research Report

Machado-Joseph病原因遺伝子(MJD1)の不安定性について

Principal Investigator

滝山 嘉久 自治医科大学, 医学部, 助手 (00245052)

Research Products

[Publications] Takiyama Y: "Machado-Joseph diseas : cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expanded allele (56 CAG repeat units) of the MJD1 gene." Neurology. (in press).

[Publications] Zhou YX: "Machado-Joseph disease in four Chinese pedigrees : molecular analysis of 15 patients including 2 juvenile cases and clinical correlations." Neurology. 48. 480-482 (1997)

[Publications] Igarashi S: "Intergenerational instability of the CAG repeat of the gene for Machado-Joseph diseas (MJD1) is affected by the genotype of the normal chromosome : implication for the molecular mechanisms of the instability of the CAG repeat" Hum Mol Genet. 5. 923-932 (1996)

[Publications] Endo K: "Strong Linkage disequilibrium and haplotype analysis in Japanese pedigrees with Machado-Joseph disease (MJD)." Am J Med Genet. (in press).

[Publications] Ikeuchi T: "Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD): mutant allele is preferentially transmitted in male meiosis." Am J Hum Genet. 58. 730-733 (1996)

[Publications] Ishikawa K: "Pure cerebellar ataxia phenotype in Machado-Joseph disease." Neurology. 46. 1776-1777 (1996)

[Publications] Sanpei K: "Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique,DIRECT." Nature Genet. 14. 277-284 (1996)

[Publications] 滝山嘉久: "キーワード1997-98´神経変性疾患(分担執筆)Machado-Joseph病" 先端医学社 水野美邦編(印刷中),

滝山嘉久自治医科大学, 医学部, 助手 (00245052)

[Publications] 滝山嘉久: "キーワード1997-98´神経変性疾患(分担執筆)Machado-Joseph病" 先端医学社水野美邦編(印刷中),