Analysis of mRNA metabolisms and therapeutic interventions for defects in neuromuscular signal transduction

• Project/Area Number: 21390266
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: OHNO Kinji 名古屋大学, 大学院・医学系研究科, 教授 (80397455)
• Co-Investigator(Kenkyū-buntansha): MASUDA Akio 名古屋大学, 大学院・医学系研究科, 助教 (10343203) ; ITO Mikako 名古屋大学, 大学院・医学系研究科, 助教 (60444402)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2011: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 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

Research Abstract

We previously reported a splicing mutation in exon P3A of CHRNA1. We here identified that hnRNP L binds to the mutant site and suppresses splicing of exon P3A. We also reported that intravenous and intramuscular administration of AAV-COLQ to Colq-/-mice improved motor functions, as well as electrophysiological, histochemical, and biochemical features.

Research Products

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