神経筋接合分子欠損症におけるmRNA病態研究と治療法開発研究

• 研究課題/領域番号: 21390266
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 神経内科学
• 研究機関: 名古屋大学
• 研究代表者: 大野 欽司 名古屋大学, 大学院・医学系研究科, 教授 (80397455)
• 研究分担者: 増田 章男 名古屋大学, 大学院・医学系研究科, 助教 (10343203) ; 伊藤 美佳子 名古屋大学, 大学院・医学系研究科, 助教 (60444402)
• 研究期間 (年度): 2009 – 2011
• 研究課題ステータス: 完了 (2011年度)
• 配分額: 17,810千円 (直接経費: 13,700千円、間接経費: 4,110千円); 2011年度: 5,720千円 (直接経費: 4,400千円、間接経費: 1,320千円); 2010年度: 5,720千円 (直接経費: 4,400千円、間接経費: 1,320千円); 2009年度: 6,370千円 (直接経費: 4,900千円、間接経費: 1,470千円)
• キーワード: 先天性筋無力症候群 / スプライシング異常 / protein-anchoring therapy / 終板アセチルコリンエステラーゼ欠損症 / Collagen Q / アセチルコリン受容体 / スプライシングトランス因子 / hnRNP L / hnRNP LL

研究概要

先天性筋無力症候群において同定をしたアセチルコリン受容体αサブユニット遺伝子CHRNA1のスプライシング変異部位にスプライシング抑制因子hnRNP Lが結合をすることを同定した。次に、先天性筋無力症候群の一型である終板アセチルコリンエステラーゼ欠損症モデルマウスに対してAAV-COLQウィルスによるタンパク標的治療法が著効を示すことを、行動解析に加えて電気生理学的、組織化学的、生化学的に検証し報告した。

研究成果

• [雑誌論文] A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes (2012)
  • 著者名/発表者名: Yoshinaga H, Sakoda S, Good JM, Takahashi MP, Kubota T, Arikawa-Hirasawa E, Nakata T, OhnoK, Kitamura T, Kobayashi K, Ohtsuka Y
  • 雑誌名: J Neurol Sci 巻: 315 ページ: 15-19
  • 査読あり
• [雑誌論文] CUGBP1 and MBNL1 preferentially bind to 3' UTRs and facilitate mRNA decay (2012)
  • 著者名/発表者名: Masuda A, Andersen HS, Doktor TK, Okamoto T, Ito M, Andresen BS, Ohno K
  • 雑誌名: Scientific Reports 巻: 2 ページ: 209-209
  • 査読あり
• [雑誌論文] Myotonic dystrophy type 2 (DM2) is rare in the Japanese population (2012)
  • 著者名/発表者名: Matsuura T, Minami N, Arahata H, Ohno K, Abe K, Hayashi YK, Nishino I
  • 雑誌名: J Hum Genet 巻: (印刷中) 号: 3 ページ: 219-220
  • DOI: 10.1038/jhg.2011.152
  • 査読あり
• [雑誌論文] Protein-anchoring strategy for delivering acetylcholinesterase to the neuromuscular junction (2012)
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 雑誌名: Mol Ther 巻: (印刷中) 号: 7 ページ: 1384-1392
  • DOI: 10.1038/mt.2012.34
  • 査読あり
• [雑誌論文] Anti-MuSK autoantibodies block binding of collagen Q to MuSK (2011)
  • 著者名/発表者名: Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, Nishida H, Mabuchi N, Engel A G, Ohno K
  • 雑誌名: Neurology 巻: 77 ページ: 1819-1826
  • 査読あり
• [雑誌論文] Hyperuricemia cosegregating with osteogenesis imperfecta is associated with amutation in (2011)
  • 著者名/発表者名: Kaneko H, Kitoh H, Matsuura T, Masuda A, Ito M, Mottes M, Rauch F, Ishiguro N, Ohno K
  • 雑誌名: GPATCH8 巻: 130 ページ: 671-683
  • 査読あり
• [雑誌論文] Molecular hydrogen inhibits lip polysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages (2011)
  • 著者名/発表者名: Itoh T, Hamada N, Terazawa R, Ito M, Ohno K, Ichihara M, Nozawa Y, Ito M
  • 雑誌名: Biochem Biophys Res Commun 巻: 411 ページ: 143-149
  • 査読あり
• [雑誌論文] AG-dependent 3'-splice sites are predisposed to aberrant splicing due to amutation at the first nucleotide of an exon (2011)
  • 著者名/発表者名: Fu Y, Masuda A, Ito M, Shinmi J, Ohno K
  • 雑誌名: Nucleic Acids Research 巻: 39 ページ: 4396-4404
  • 査読あり
• [雑誌論文] Myasthenic syndrome caused by plectinopathy (2011)
  • 著者名/発表者名: Selcen D, Juel VC, Hobson-Webb LD, Smith EC, Stickler DE, Bite AV, Ohno K, Engel AG
  • 雑誌名: Neurology 巻: 76 ページ: 327-336
  • 査読あり
• [雑誌論文] AG-dependent 3'-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon (2011)
  • 著者名/発表者名: Fu Y, Masuda A, Ito M, Shinmi J, Ohno K
  • 雑誌名: Nucleic Acids Research 巻: 39 号: 10 ページ: 4396-4404
  • DOI: 10.1093/nar/gkr026
  • 査読あり
• [雑誌論文] Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages (2011)
  • 著者名/発表者名: Itoh T, Hamada N, Terazawa R, Ito M, Ohno K, Ichihara M, Nozawa Y, Ito M
  • 雑誌名: Biochem Biophys Res Commun 巻: 411 号: 1 ページ: 143-149
  • DOI: 10.1016/j.bbrc.2011.06.116
  • 査読あり
• [雑誌論文] Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8 (2011)
  • 著者名/発表者名: Kaneko H, Kitoh H, Matsuura T, Masuda A, Ito M, Mottes M, Rauch F, Ishiguro N, Ohno K
  • 雑誌名: Hum Genet 巻: 130 号: 5 ページ: 671-683
  • DOI: 10.1007/s00439-011-1006-9
  • 査読あり
• [雑誌論文] Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of CHRNA1 exon P3Adue to an hnRNP H-disrupting mutation in congenital myasthenic syndrome (2009)
  • 著者名/発表者名: Bian Y, Masuda A, Matsuura T, Ito M, Okushin K, Engel AG, Ohno K
  • 雑誌名: Hum Mol Genet 巻: 18 ページ: 1229-1237
  • 査読あり
• [雑誌論文] Myasthenic syndrome due to defects in rapsyn : Clinical and molecular findings in 39 patients (2009)
  • 著者名/発表者名: Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG
  • 雑誌名: Neurology 巻: 73 ページ: 228-235
  • 査読あり
• [雑誌論文] Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells (2009)
  • 著者名/発表者名: Itoh T, Fujita Y, Ito M, Masuda A, Ohno K, Ichihara M, Kojima T, Nozawa Y, Ito M.
  • 雑誌名: Biochem Biophys Res Commun Vol. 389 ページ: 651-656
  • 査読あり
• [雑誌論文] Alu-mediated acquisition of unstable ATTCT pentanucleotide repeats in the human ATXN10 gene (2009)
  • 著者名/発表者名: Kurosaki T, Matsuura T, Ohno K, Ueda S.
  • 雑誌名: Mol Biol Evol Vol. 26 ページ: 2573-2579
  • 査読あり
• [雑誌論文] Myasthenic syndrome due to defects in rapsyn : Clinical and molecular findings in 39 patients (2009)
  • 著者名/発表者名: Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG.
  • 雑誌名: Neurology Vol. 73 ページ: 228-235
  • 査読あり
• [雑誌論文] Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10) (2009)
  • 著者名/発表者名: Almeida T, Alonso I, Martins S, Ramos EM, Azevedo L, Ohno K, Amorim A, Saraiva-Pereira ML, Jardim LB, Matsuura T, Sequeiros J, Silveira I.
  • 雑誌名: PLoS ONE Vol. 4
  • 査読あり
• [雑誌論文] Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of CHRN A1 exon P3A due to an hnRNP H-disrupting mutation in congenital myasthenic syndrome (2009)
  • 著者名/発表者名: Bian Y, Masuda A, Matsuura T, Ito M, Okushin K, Engel AG, Ohno K.
  • 雑誌名: Hum Mol Genet Vol. 18 ページ: 1229-1237
  • 査読あり
• [雑誌論文] Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease (2009)
  • 著者名/発表者名: Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A, Suzuki Y, Maesawa S, Kajita Y, Hirayama M, Ohsawa I, Ohta S, Ohno K.
  • 雑誌名: Neurosci Lett Vol. 453 ページ: 81-85
  • 査読あり
• [雑誌論文] Protein-anchoring strategy for delivering acetyl cholinesterase to the neuromuscular junction
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, FukudomeT, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 雑誌名: Mol Ther 巻: (in press)
  • 査読あり
• [雑誌論文] Myotonic dystrophy type 2(DM2) is rare in the Japanese populatio
  • 著者名/発表者名: Matsuura T, Minami N, Arahata H, Ohno K, Abe K, Hayashi YK, Nishino I
  • 雑誌名: J Hum Genet in press
  • 査読あり
• [学会発表] Anti-MuSK antibodies in myastheniagravis block binding of collagen Q toMuSK expressed at theneuromuscular junction (2011)
  • 著者名/発表者名: Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, Hishida H, Mabuchi N, Engel AG
  • 学会等名: 41st Annual Meeting, Society for Neuroscience
  • 発表場所: Washington DC, USA
  • 年月日: 2011-11-15
• [学会発表] Anti-MuSK antibodies in myasthenia gravis block binding of collagen Q to MuSK expressed at the neuromuscular junction (2011)
  • 著者名/発表者名: Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, Hishida H, Mabuchi N, Engel AG, Ohno K
  • 学会等名: 41st Annual Meeting, Society for Neuroscience
  • 発表場所: Washington DC, USA
  • 年月日: 2011-11-15
• [学会発表] Protein-anchoring therapy for delivering acetylcholinesterase to theneuromuscular junction (2011)
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 学会等名: 4th International Congress of Myology
  • 発表場所: Lille, France
  • 年月日: 2011-05-09
• [学会発表] Protein-anchoring therapy for delivering acetylcholinesterase to the neuromuscular junction (2011)
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 学会等名: 4th International Congress of Myology
  • 発表場所: Lille, France(招待講演)
  • 年月日: 2011-05-09
• [学会発表] Mutations at the C-terminal domain(CTD) of collagen Q(ColQ) causingacetylcholinesterase(AChE) deficiencyprevent anchoring of ColQ to theneuromuscular junction(NMJ) (2010)
  • 著者名/発表者名: Sugiyama A, Ito M, Nakata T, Azuma Y, Masuda A, Okumura A, Komaki H, Ohno K
  • 学会等名: Mutations at the C-terminal domain(CTD) of collagen Q(ColQ) causingacetylcholinesterase(AChE) deficiencyprevent anchoring of ColQ to theneuromuscular junction(NMJ)
  • 発表場所: San Diego, USA
• [学会発表] rAAV8-Mediated Protein-Anchoring Therapy for Targeting Collagen Q-Tailed Acetylcholinesterase to the Neuromuscular Junction (2010)
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, FukudomeT, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 学会等名: American Society of Gene & Cell Therapy 13th Annual Meeting, Washington DC
  • 発表場所: USA
• [学会発表] rAAV8-Mediated Protein-Anchoring Therapy for Targeting Collagen Q-Tailed Acetylcholinesterase to the Neuromuscular Junction (2010)
  • 著者名/発表者名: Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • 学会等名: American Society of Gene & Cell Therapy 13th Annual Meeting
  • 発表場所: Washington DC, USA
• [学会発表] Mutations at the C-terminal domain (CTD) of collagen Q (ColQ) causing acetylcholinesterase (AChE) deficiency prevent anchoring of ColQ to the neuromuscular junction (NMJ) (2010)
  • 著者名/発表者名: Sugiyama A, Ito M, Nakata T, Azuma Y, Masuda A, Okumura A, Komaki H, Ohno K
  • 学会等名: 40th Annual Meeting, Society for Neuroscience
  • 発表場所: San Diego, USA
• [学会発表] Molecular mechanisms and regulations of congenital neuromuscular transmission defects (2009)
  • 著者名/発表者名: Ohno K
  • 学会等名: Universite Paris Descartes Seminaire
  • 発表場所: Paris, France
  • 年月日: 2009-07-06
• [学会発表] Degeneracy of splicing cis-elements and tolerance to disease-causing mutations (2009)
  • 著者名/発表者名: Ohno K
  • 学会等名: 2nd GCOE International Symposium
  • 発表場所: Nagoya, Japan
• [学会発表] A mutation on a nonfunctional exon P3A inCHRNA1 identified in a patient withcongenital myasthenic syndrome losesbinding affinity for a splicing-suppressinghn RNP L and gains binding affinity for asplicing-enhancing RNP LL (2009)
  • 著者名/発表者名: Rahman MA, Masuda A, Ito M, Ohno K
  • 学会等名: 2nd GCOE International Symposium
  • 発表場所: Nagoya, Japan
• [学会発表] AG-independence of the 3'splice site determines tolerance to aberrant splicingdue to a mutation at the first nucleotide of an exon (2009)
  • 著者名/発表者名: Fu Y, Masuda A, Ito M, Ohno K
  • 学会等名: 2nd GCOE International Symposium
  • 発表場所: Nagoya, Japan
• [学会発表] Protein anchoring therapy for endplateacetylcholinesterase deficiency (2009)
  • 著者名/発表者名: Ohno K, Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Takeda S, Krejci E
  • 学会等名: Eighth French-Japanese Workshop on Muscular Dystrophies
  • 発表場所: Paris, France
• [図書] Congenital myasthenic syndromes. Myasthenia gravis and myasthenic disorders 2nd ed.(Ed.by Engel AG) (2012)
  • 著者名/発表者名: Engel AG, Shen X-M, Ohno K, Sine SM
  • 出版者: Oxford University Press, New York(in press)
• [図書] Congenital Myasthenic Syndromes-Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction-Myopathy (2012)
  • 著者名/発表者名: Ohno K, Ito M, Engel AG
  • 出版者: InTech, Rijeka(in press)(査読有)
• [図書] Chapter 8 : Molecular defects of acetylcholine receptor subunits in congenital myasthenic syndromes. Pharmacology of Nicotinic Acetylcholine Receptors from the Basic and Therapeutic Perspectives (2011)
  • 著者名/発表者名: Ohno K, Engel AG
  • 出版者: Research Signpost, Kerala
• [図書] RNA pathologies in neurological disorders. Neurochemical Mechanisms in Disease, Advances in Neurobiology (2011)
  • 著者名/発表者名: Ohno K, Masuda A
  • 出版者: Springer, New York
• [図書] RNA pathologies in neurological disorders. Neurochemical Mechanisms in Disease, Advances in Neurobiology(Ed by Abel Lajtha) (2011)
  • 著者名/発表者名: Ohno K, Masuda A
  • 出版者: Springer, New York
• [図書] Chapter 8 : Molecular defects of acetylcholine receptor subunits in congenital myasthenic syndromes. Pharmacology of Nicotinic Acetylcholine Receptors from the Basic and Therapeutic Perspectives(Ed.By Hugo R.Arias) (2011)
  • 著者名/発表者名: Ohno K, Engel AG
  • 出版者: Research Signpost, Kerala
• [図書] Congenital Myasthenic Syndromes-Molecular Bases of Congenital Defects of Proteins at the NeuromuscularJunction- Myopathy
  • 著者名/発表者名: Ohno K, Ito M, Engel AG
  • 出版者: InTech, Rijeka(in press)
• [図書] Congenital myasthenicsyndromes. Myasthenia gravis and myasthenic disorders 2nd ed. Ed. byEngel AG
  • 著者名/発表者名: Engel AG, Shen X-M, Ohno K, Sine SM
  • 出版者: Oxford University Press,New York(in press)