Identification of target molecules against anti MuSK IgG in Myasthenia Gravis

• Project/Area Number: 23700422
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Nagoya University
• Principal Investigator: ITO Mikako 名古屋大学, 医学(系)研究科(研究院), 助教 (60444402)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 重症筋無力症 / MuSK / Collagen Q / LRP4 / 筋・末梢神経疾患 / 国際研究者交流 / パリ / アセチルコリンエステラーゼ

Research Abstract

Myasthenia Gravis (MG) is antoimmuno disease caused by an antoantibody to protein consisting of neuromuscular junction. Anti MuSK MG account for fifteen percent of MG ,but it is unclear well. MuSK is membrane transfer protein of NMJ, and has Ig1, Ig2, Ig3, Ig4 and C6 box in extracellar region. In this study, it was demonstrated that anti-MuSK antibody from five persons inhibit both MuSK-ColQ and MuSK-LRP4 interaction. Moreover, MuSK antibody recognizes Ig1 and Ig4, and LRP4 also binds Ig1 and Ig4.

Research Products

• [Journal Article] LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated musk signaling in a position-specific manner (2014)
  • Author(s): Ohkawara, B., Cabrera-Serrano, M., Nakata, T., Milone, M., Asai, N., Ito, K., Ito, M., Masuda, A., Ito, Y., Engel, A. G. and Ohno, K.
  • Journal Title: Hum. Mol. Genet. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in utero ischemia-reperfusion (2014)
  • Author(s): Mano, Y., Kotani, T., Ito, M., Nagai, T., Ichinohashi, Y., Yamada, K., Ohno, K., Kikkawa, F. and Toyokuni, S.
  • Journal Title: Free Radic. Biol. Med. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling (2014)
  • Author(s): Takamatsu, A., Ohkawara, B., Ito, M., Masuda, A., Sakai, T., Ishiguro, N. and Ohno, K.
  • Journal Title: PLOS ONE Volume: (in press)
  • Peer Reviewed
• [Journal Article] Collagen Q is a key player for developing rational therapy for congenital myasthenia and for dissecting the mechanisms of anti-MuSK myasthenia gravis (2014)
  • Author(s): Ohno, K., Ito, M. and Kawakami, Y.
  • Journal Title: J. Mol. Neurosci. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in utero ischemia-reperfusion. (2014)
  • Author(s): Mano, Y., Kotani, T., Ito, M., Nagai, T., Ichinohashi, Y., Yamada, K., Ohno, K., Kikkawa, F. and Toyokuni, S.
  • Journal Title: Free Radic. Biol. Med. Volume: in press
  • Peer Reviewed
• [Journal Article] Collagen Q is a key player for developing rational therapy for congenital myasthenia and for dissecting the mechanisms of anti-MuSK myasthenia gravis. (2014)
  • Author(s): Ohno, K. and Ito, M. and Kawakami, Y.
  • Journal Title: Mol. Neurosci Volume: in press
• [Journal Article] Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling. (2014)
  • Author(s): Takamatsu, A., Ohkawara, B., Ito, M., Masuda, A., Sakai, T., Ishiguro, N. and Ohno, K.
  • Journal Title: PLOS ONE Volume: 9(3) Issue: 3 Pages: e92699-e92699
  • DOI: 10.1371/journal.pone.0092699
  • Peer Reviewed / Open Access
• [Journal Article] Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia (2013)
  • Author(s): Matsushita, M., Kitoh, H., Ohkawara, B., Mishima, K., Kaneko, H., Ito, M., Masuda, A., Ishiguro, N. and Ohno, K.
  • Journal Title: PLoS ONE Volume: 8(12)
  • Peer Reviewed
• [Journal Article] HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA (2013)
  • Author(s): Rahman, M. A., Masuda, A., Ohe, K., Ito, M., Hutchinson, D. O., Mayeda, A., Engel, A. G. and Ohno, K.
  • Journal Title: Sci. Rep. Volume: (3) Pages: 2931-2931
  • Peer Reviewed
• [Journal Article] Mutations in the C-Terminal Domain of ColQ in Endplate Acetylcholinesterase Deficiency Compromise ColQ-MuSK Interaction (2013)
  • Author(s): Nakata T, Ito M, Azuma Y, Otsuka K, Noguchi Y, Komaki H, Okumura A, Shiraishi K, Masuda A, Natsume J, Kojima S, Ohno K
  • Journal Title: Hum Mutat. Volume: 34(7) Pages: 997-1004
  • Peer Reviewed
• [Journal Article] Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells (2013)
  • Author(s): Iio A, Ito M, Itoh T, Terazawa R, Fujita Y, Nozawa Y, Ohsawa I, Ohno K, Ito M
  • Journal Title: Med Gas Res. Volume: 3(1) Pages: 6-6
  • Peer Reviewed
• [Journal Article] Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice (2013)
  • Author(s): Yamamoto R, Matsushita M, Kitoh H, Masuda A, Ito M, Katagiri T, Kawai T, Ishiguro N, Ohno K
  • Journal Title: J Bone Miner Metab. Volume: 31(1) Pages: 26-33
  • Peer Reviewed
• [Journal Article] Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis (2013)
  • Author(s): Ohno K, Ito M, Kawakami Y, Krejci E, Engel A.G
  • Journal Title: Chem Biol Interact. Volume: 25;203(1) Pages: 335-340
  • Peer Reviewed
• [Journal Article] Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. (2013)
  • Author(s): Matsushita, M., Kitoh, H., Ohkawara, B., Mishima, K., Kaneko, H., Ito, M., Masuda, A., Ishiguro, N. and Ohno, K.
  • Journal Title: PLOS ONE Volume: 8(12) Issue: 12 Pages: 81569-81569
  • DOI: 10.1371/journal.pone.0081569
  • Peer Reviewed
• [Journal Article] HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. (2013)
  • Author(s): Rahman, M. A., Masuda, A., Ohe, K., Ito, M. , Hutchinson, D. O., Mayeda, A., Engel, A. G. and Ohno, K.
  • Journal Title: Sci. Rep. Volume: 3 Issue: 1 Pages: 2931-2931
  • DOI: 10.1038/srep02931
  • Peer Reviewed
• [Journal Article] Mutations in the C-Terminal Domain of ColQ in Endplate Acetylcholinesterase Deficiency Compromise ColQ-MuSK Interaction. (2013)
  • Author(s): Nakata T, Ito M, Azuma Y, Otsuka K, Noguchi Y, Komaki H, Okumura A, Shiraishi K, Masuda A, Natsume J, Kojima S, Ohno K.
  • Journal Title: Human Mutation Volume: in press Issue: 7 Pages: 997-1004
  • DOI: 10.1002/humu.22325
  • Peer Reviewed
• [Journal Article] Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells (2013)
  • Author(s): Iio A, Ito M, Itoh T, Terazawa R, Fujita Y, Nozawa Y, Ohsawa I, Ohno K, Ito M
  • Journal Title: Med Gas Res Volume: 3 Issue: 1 Pages: 6-6
  • DOI: 10.1186/2045-9912-3-6
  • Peer Reviewed
• [Journal Article] Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice (2013)
  • Author(s): Yamamoto R, Matsushita M, Kitoh H, Masuda A, Ito M, Katagiri T, Kawai T, Ishiguro N, Ohno K
  • Journal Title: J Bone Miner Metab Volume: 31 Pages: 26-33
  • DOI: 10.1007/s00774-012-0380-2
  • NAID: 10031168834
  • Peer Reviewed
• [Journal Article] Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy (2012)
  • Author(s): Yamashita Y, Matsuura T, Shinmi J, Amakusa Y, Masuda A, Ito M, Kinoshita M, Furuya H, Abe K, Ibi T, Sahashi K, Ohno K
  • Journal Title: J Hum Genet. Volume: 57(6) Pages: 368-74
  • 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: Molecular Therapy Volume: 20(7) Pages: 1384-1392
  • 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] Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson's disease in rats (2012)
  • Author(s): Ito M, Hirayama M, Yamai K, Goto S, Ito M, Ichihara M and Ohno K
  • Journal Title: Medical Gas Research Volume: 2 Pages: 15-15
  • Peer Reviewed
• [Journal Article] Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson's disease (2012)
  • Author(s): Hirayama M, Nakamura T, Watanabe H, Uchida K, Hama T, Hara T, Niimi Y, Ito M, Ohno K, Sobue G
  • Journal Title: Parkinsonism Relat Disord Volume: 17 Pages: 46-49
  • 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] Four parameters increase the sensitivity and specificity of the exon array analysis and disclose twenty-five novel aberrantly spliced exons in myotonic dystrophy. (2012)
  • Author(s): Yamashita Y, Matsuura T, Shinmi J, Amakusa Y, Masuda A, Ito M, Kinoshita M, Furuya H, Abe K, Ibi T, Sahashi K, Ohno K.
  • Journal Title: Journal of Human Genetics Volume: 57 Issue: 6 Pages: 368-374
  • DOI: 10.1038/jhg.2012.37
  • Peer Reviewed
• [Journal Article] Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies (2011)
  • Author(s): Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K
  • Journal Title: Medical Gas Research Volume: 1 Pages: 24-24
  • 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(20) Pages: 1819-26
  • 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: Human Genetics Volume: 130(5) Pages: 671-683
  • Peer Reviewed
• [Journal Article] Molecular hydrogen inhibits lipopolysaccharide/interferon c-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 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 Res. Volume: 39 Pages: 4396-4404
  • 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] Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. (2011)
  • Author(s): Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K
  • Journal Title: Medical Gas Research Volume: 1
  • Peer Reviewed
• [Journal Article] Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson's disease (2011)
  • Author(s): Hirayama M, Nakamura T, Watanabe H, Uchida K, Hama T, Hara T, Niimi Y, Ito M, Ohno K, Sobue G.
  • Journal Title: Parkinsonism Relat Disord Volume: 17 Pages: 46-49
  • Peer Reviewed
• [Presentation] Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction, ポスター発表 (2013)
  • Author(s): Ito M, Nakata T, Azuma Y, Otsuka K, Noguchi Y, Komaki H, Okumura A, Shiraishi K, Masuda A, Natsume J, Kojima S, Ohno K
  • Organizer: XIV International symposium on Cholinergic Mechanisms
  • Place of Presentation: Hangzhou China
  • Year and Date: 2013-05-06
• [Presentation] Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction. (2013)
  • Author(s): Ito M, Nakata T, Azuma Y, Otsuka K, Noguchi Y, Komaki H, Okumura A, Shiraishi K, Masuda A, Natsume J, Kojima S, Ohno K
  • Organizer: XIV International symposium on Cholinergic Mechanisms
  • Place of Presentation: Hangzhou China
• [Presentation] Protein-anchoring therapy for delivering acetylcholinesterase to the neuromuscular junction, ポスター発表 (2012)
  • Author(s): Ito M., Suzuki Y., Okada T., Fukudome T., Yoshimura T., Masuda A., Takeda S., Krejci E., Ohno K.
  • Organizer: 11th Cholinesterase meeting
  • Place of Presentation: Kazan Russia
  • Year and Date: 2012-06-07
• [Presentation] 水素水飲用をシミュレーションする水素ガス間欠投与は、水素ガス持続投与よりもパーキンソンモデルラットに対して有効である, 口頭発表 (2012)
  • Author(s): 伊藤美佳子、市原正智、伊藤雅史、大野欽司
  • Organizer: 第3回分子状水素医学シンポジウム
  • Place of Presentation: 北里大学薬学部コンベンションホール東京都港区
  • Year and Date: 2012-02-09
• [Presentation] PROTEIN-ANCHORING THERAPY FOR DELIVERING ACETYLCHOLINESTERASE TO THE NEUROMUSCULAR JUNCTION, ポスター発表 (2011)
  • Author(s): Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K
  • Organizer: 日本遺伝子治療学会
  • Place of Presentation: 九州大学医学部百年講堂福岡市
  • Year and Date: 2011-07-16
• [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: 日本遺伝子治療学会
  • Place of Presentation: 九州大学
• [Book] Congenital Myasthenic Syndromes . Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction (2012)
  • Author(s): Kinji Ohno, Mikako Ito, Andrew G. Engel
  • Total Pages: 270
  • Publisher: Myopathy, InTech (ISBN 978-953-51-0696-8)
• [Book] Myopathy (2012)
  • Author(s): Kinji Ohno, Mikako Ito, Andrew G. Engel
  • Total Pages: 270
  • Publisher: Congenital Myasthenic Syndromes – Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/neurogenetics/
• [Remarks] 名古屋大学 医学系研究科 先端応用医学部門 神経遺伝情報学
  • URL: http://www.med.nagoya-u.ac.jp/neurogenetics/