Molecular bases and their regulations of mRNA aberrations in neuromuscular transmission defects and other muscular diseases

• Project/Area Number: 19390237
• 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 Nagoya University, 大学院・医学系研究科, 教授 (80397455)
• Co-Investigator(Kenkyū-buntansha): MATSUURA Tohru 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (90402560) ; MASUDA Akio 名古屋大学, 大学院・医学系研究科, 助教 (10343203)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 先天性筋無力症候群 / スプライシング異常 / タンニン酸 / 遺伝子 / ゲノム / 神経科学 / マイクロアレイ

Research Abstract

先天性筋無力症候群の原因となるCHRNA1 IVS3-8G>A遺伝子変異は、スプライシングトランス因子hnRNPHとシス因子との結合を100倍減弱することを明らかにした。この研究の過程でIVS3-8G上流領域にスプライシング抑制因子PTBP1が結合することを同定し、960種類のFDA既認可薬を用いたスクリーニングにてタンニン酸が濃度依存性にPTBP1プロモータを活性化させIVS3-8G>Aによる異常スプライシングを是正することを見出した。

Research Products

• [Journal Article] hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome (2008)
  • Author(s): Masuda A, Shen XM, Ito M, Matsuura T, Engel AG, Ohno K
  • Journal Title: Hum Mol Genet 17 Pages: 4022-4035
  • Peer Reviewed
• [Journal Article] Congenital myasthenia-related AChR delta subunit mutation interferes with intersubunit communication essential for channel gating (2008)
  • Author(s): Shen X-M, Fukuda T, Ohno K, Sine SM, Engel AG
  • Journal Title: J Clin Invest 118 Pages: 1867-1876
  • Peer Reviewed
• [Journal Article] Human branch point consensus sequence is yunay (2008)
  • Author(s): Gao K, Masuda A, Matsuura T, Ohno K
  • Journal Title: Nucleic Acids Res 36 Pages: 2257-2267
  • Peer Reviewed
• [Journal Article] Long-range PCR for the diagnosis of spinocerebellar ataxia type 10 (2008)
  • Author(s): Kurosaki T, Matsuura T, Ohno K, Ueda S
  • Journal Title: Neurogenetics 9 Pages: 151-152
  • Peer Reviewed
• [Journal Article] Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families (2008)
  • Author(s): Saito T, Amakusa Y, Kimura T, Yahara O, Aizawa H, Ikeda Y, Day JW, Ranum LPW, Ohno K, Matsuura T
  • Journal Title: Neurogenetics 9 Pages: 61-63
  • Peer Reviewed
• [Journal Article] hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome (2008)
  • Author(s): Masuda A, Shen XM, Ito M, Matsuura T, Engel AG, Ohno K
  • Journal Title: Hum Mol Genet Vol.17 Pages: 4022-4035
  • Peer Reviewed
• [Journal Article] Congenital myasthenia-related AChR delta subunit mutation interferes with intersubunit communication essential for channel gating (2008)
  • Author(s): Shen X-M, Fukuda T, Ohno K, Sine SM, Engel AG.
  • Journal Title: J Clin Invest Vol.118 Pages: 1867-1876
  • Peer Reviewed
• [Journal Article] Human branch point consensus sequence is yUnAy (2008)
  • Author(s): Gao K, Masuda A, Matsuura T, Ohno K.
  • Journal Title: Nucleic Acids Res Vol.36 Pages: 2257-2267
  • Peer Reviewed
• [Journal Article] Long-range PCR for the diagnosis of spinocerebellar ataxia type 10 (2008)
  • Author(s): Kurosaki T, Matsuura T, Ohno K, Ueda S.
  • Journal Title: Neurogenetics Vol.9 Pages: 151-152
  • Peer Reviewed
• [Journal Article] Myotonic dystrophy type 2 in Japan : ancestral origin distinct from Caucasian families (2008)
  • Author(s): Saito T, Amakusa Y, Kimura T, Yahara O, Aizawa H, Ikeda Y, Day JW, Ranum LPW, Ohno K, Matsuura T.
  • Journal Title: Neurogenetics Vol.9 Pages: 61-63
  • Peer Reviewed
• [Journal Article] Novel AChR δ subunit mutation causing myasthenia hinders intersubunitlink essential for channel gating. (2008)
  • Author(s): Shen X-M
  • Journal Title: J Clin Invest (in press)
  • Peer Reviewed
• [Journal Article] Thermodynamic instability of siRNA duplex is a prerequisite for dependable prediction of siRNA activities (2007)
  • Author(s): Ichihara M, Murakumo Y, Masuda A, Matsuura T, Asai N, Jijiwa M, Ishida M, Shinmi J, Yatsuya H, Qiao S, Takahashi M, Ohno K
  • Journal Title: Nucleic Acids Res 35
  • Peer Reviewed
• [Journal Article] In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5' splice sites (2007)
  • Author(s): Sahashi K, Masuda A, Matsuura T, Shinmi J, Zhang Z, Takeshima Y, Matsuo M, Sobue G, Ohno K
  • Journal Title: Nucleic Acids Res 35 Pages: 5995-6003
  • Peer Reviewed
• [Journal Article] Essential role of GATA transcriptional factors in the activation of mast cells (2007)
  • Author(s): Masuda A, Hashimoto K, Yokoi T, Doi, T, Kodama, T, Kume, H, Ohno, K, Matsuguchi, T
  • Journal Title: J Immunol 178 Pages: 360-368
  • Peer Reviewed
• [Journal Article] In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5' splice sites. (2007)
  • Author(s): Sahashi K
  • Journal Title: Nucleic Acids Res 35 Pages: 5995-6003
  • Peer Reviewed
• [Journal Article] Thermodynamic instability of siRNA duplex is a prerequisite for dependable prediction of siRNA activities. (2007)
  • Author(s): Ichihara M
  • Journal Title: Nucleic Acids Res 35
  • Peer Reviewed
• [Presentation] rAAV8-mediated protein anchoring of asymmetric acetylcholinesterase (AChE) to the synaptic basal lamina at the neuromuscular junction (NMJ) (2008)
  • Author(s): Ito M, Suzuki Y, Okada T, Fukudome T, Masuda A, Yoshimura T, Takeda S, Krejci E, Ohno K
  • Organizer: 48th Annual Meeting of the American Society for Cell Biology
  • Place of Presentation: San Francisco, USA
• [Presentation] Adeno-associated virus serotype 8-mediated targeting of asymmetric acetylcholinesterase to the synaptic basal lamina at the neuromuscular junction (2008)
  • Author(s): Ito M, Suzuki Y, Okada T, Fukudome T, Masuda A, Yoshimura T, Takeda S, Krejci E, Ohno K
  • Organizer: 38th Annual Meeting, Society for Neuroscience
  • Place of Presentation: Washington DC, USA
• [Presentation] CMS due to Defects in Rapsyn: Clinical and Molecular Findings of a Large Cohort (2008)
  • Author(s): Milone M, Shen X-M, Selcen D, Ohno K, Brengman JM, Iannaccone S, Engel AG
  • Organizer: 55th Annual Meeting of the American Association of Neuromuscular and Electrodiagnostic medicine
  • Place of Presentation: Rhode Island, USA
• [Presentation] Recombinant extracellular matrix protein expressed in a limited number of cells propagates to the target organ throughout the body using its nascent tissue-targeting signal (2008)
  • Author(s): Suzuki Y, Ito M, Okada T, Takeda S, Fukudome T, Yoshimura T, Krejci E, Ohno K
  • Organizer: 13th Congress of the International Federation of Societies for Histochemistry and Cytochemistry
  • Place of Presentation: Gdansk, Poland
• [Presentation] CMS due to defects in rapsyn: clinical and molecular findings of a large cohort (2008)
  • Author(s): Milone M, Shen X-M, Selcen D, Ohno K, Brengman JM, Iannaccone S, Engel AG
  • Organizer: 12th Congress of the European Federation of Neurological Societies
  • Place of Presentation: Madrid, Spain
• [Presentation] Gene Therapy for Collagen Q defects in congenital myasthenic syndromes (2007)
  • Author(s): Ito M, Masuda A, Jinno S, Katagiri T, Krejci E, Ohno K
  • Organizer: The IXth International Meeting on Cholinesterases
  • Place of Presentation: Shuzou, China
  • Year and Date: 2007-05-10
• [Presentation] Comprehensive analysis of aberrantly spliced exons in myotonic dystrophy type 1 using Affymetrix Exon Array (2007)
  • Author(s): Yamashita Y, Matsuura T, Shinmi J, Ibi T, Kinoshita M, Kimura T, Yahara O, Sahashi K, Ohno K
  • Organizer: 57th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Diego, California, USA
• [Presentation] Unstable siRNA duplex is a prerequisite for accurate prediction of siRNA efficiency-Proposal of a new parameter based on the linear regression model (2007)
  • Author(s): Ohno K, Ichihara M
  • Organizer: 57th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Diego, California, USA
• [Presentation] Myotonic dystrophy type 2 in Japan: distinct ancestral origin from Caucasian familiesne (2007)
  • Author(s): Amakusa Y, Matsuura T, Saito T, Kimura T, Yahara O, Aizawa H, Ikeda Y, Day JW, Ranum LPW, Ohno K
  • Organizer: 57th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Diego, California, USA
• [Presentation] Unstable siRNA duplex is a prerequisite for accurate prediction of siRNA efficiency-Proposal of a new parameter based on the linear regression model- (2007)
  • Author(s): Ohno K
  • Organizer: 57th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Diego, California, USA