Molecular dissection of LPR4, a molecule expressed at the neuromuscular junction

2013 Fiscal Year Final Research Report

• Project/Area Number: 25670164
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: KINJI Ohno 名古屋大学, 医学(系)研究科(研究院), 教授 (80397455)
• Co-Investigator(Kenkyū-buntansha): OHKAWARA Bisei 名古屋大学, 高等研究院, 特任講師 (80589606)
• Project Period (FY): 2013-04-01 – 2014-03-31
• Keywords: 先天性筋無力症候群 / LRP4 / Wnt / MuSK

Research Abstract

LRP4 is essential for formation and maintenance of the acetylcholine receptor clusters. Mutations in LRP4 have been reported in bone and cartilage diseases representing syndactyly and hyperostosis. We have identified that LRP4 mutations also cause a congenital myasthenic syndrome. LRP4 mutations in bone and cartilage diseases are located in the central cavity of the third beta propeller domain of LRP4, and the central cavity is essential for suppression of Wnt beta-catenin signaling. On the other hand, LRP4 mutations in a congenital myasthenic syndrome are located at the periphery of the third beta propeller domain of LRP4, and the periphery is essential for activation of agrin/LRP4/MuSK signaling leading to clustering of the acetylcholine receptor.

Research Products

• [Journal Article] LRP4 third beta-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 AG, Ohno K
  • Journal Title: Hum Mol Genet Volume: 23 Pages: 1856-1868
  • DOI: 10.1093/hmg/ddt578
  • 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 (2013)
  • Author(s): Ohno K, Ito M, Kawakami Y
  • Journal Title: J Mol Neurosci Volume: (Epub ahead of print)
  • DOI: 10.1007/s12031-013-0170-x
  • 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 Pages: 997-1004
  • DOI: 10.1002/humu.22325
  • Peer Reviewed
• [Journal Article] Gfpt1-myasthenia : Clinical, structural, and electrophysiologic heterogeneity (2013)
  • Author(s): Selcen D, Shen XM, Milone M, Brengman J, Ohno K, Deymeer F, Finkel R, Rowin J, Engel AG
  • Journal Title: Neurology Volume: 81 Pages: 370-378
  • DOI: 10.1212/WNL.0b013e31829c5e9c
  • Peer Reviewed
• [Journal Article] HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA (2013)
  • Author(s): Rahman MA, Masuda A, Ohe K, Ito M, Hutchinson DO, Mayeda A, Engel AG, Ohno K
  • Journal Title: Sci Rep Volume: 3 Pages: 2931
  • DOI: 10.1038/srep02931
  • 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 AG
  • Journal Title: Chem Biol Interact Volume: 203(1) Pages: 335-340
  • DOI: 10.1016/j.cbi.2012.08.020
  • Peer Reviewed
• [Journal Article] Exome sequencing of senescence-accelerated mice (sam) reveals deleterious mutations in degenerative disease-causing genes (2013)
  • Author(s): Tanisawa K, Mikami E, Fuku N, Honda Y, Honda S, Ohsawa I, Ito M, Endo S, Ihara K, Ohno K, Kishimoto Y, Ishigami A, Maruyama N, Sawabe M, Iseki H, Okazaki Y, Hasegawa-Ishii S, Takei S, Shimada A, Hosokawa M, Mori M, Higuchi K, Takeda T, Higuchi M, Tanaka M
  • Journal Title: BMC Genomics Volume: 14 Pages: 248
  • DOI: 10.1186/1471-2164-14-248
  • Peer Reviewed
• [Presentation] Collagen Q is a key player for developing rational therapy for congenital myasthenia and for causing anti-MuSK myasthenia gravis (2013)
  • Author(s): Ohno K, Ito M, Kawakami Y, Ohtsuka K, Krejci E
  • Organizer: XIV International Symposium on Cholinergic Mechanisms (Invited Platform)
  • Place of Presentation: Hangzhou, China
  • Year and Date: 20130505-09
• [Presentation] Mutations in LRP4 in congenital myasthenia reveal position-specific regulations of agrin and Wnt signaling of LPR4 (2013)
  • Author(s): Ohkawara B, Cabrera M, Nakata T, Shen X, Ito Y, Engel AG, Ohno K
  • Organizer: 43rd Annual Meeting Society for Neuroscience (Poster)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2013-11-13
• [Presentation] Mutations in the third β-propeller domain of LRP4 in congenital myasthenia compromise agrin-mediated MuSK signaling in a position-specific manner (2013)
  • Author(s): Ohkawara B, Cabrera M, Nakata T, Milone M, Ito Y, Engel AG, Ohno K
  • Organizer: 36th Annual Meeting of the Japan Neuroscience Society (Poster)
  • Place of Presentation: 国立京都国際会館 (京都市 )
  • Year and Date: 2013-06-22
• [Book] Molecular Genetics of Congenital Myasthenic Syndromes (2014)
  • Author(s): Ohno K, Ohkawara B, Ito M, Engel AG
  • Publisher: eLS. John Wiley & Sons, Inc., Hoboken(in press)