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

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• 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 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 AG, Ohno K
  • Journal Title: Hum Mol Genet. Volume: Apr 1;23(7) Issue: 7 Pages: 1856-68
  • DOI: 10.1093/hmg/ddt578
  • Peer Reviewed / Open Access
• [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, Kawakami Y, Ohtsuka K.
  • Journal Title: J Mol Neurosci Volume: 53(3) Issue: 3 Pages: 359-361
  • DOI: 10.1007/s12031-013-0170-x
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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 Issue: 4 Pages: 378-378
  • 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, 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] 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) Issue: 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(1): Issue: 1 Pages: 248-248
  • DOI: 10.1186/1471-2164-14-248
  • Peer Reviewed / Open Access
• [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
• [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
• [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 (Platform)
  • Place of Presentation: Hangzhou, China
  • Invited
• [Presentation] Investigation of 11 patients with GFPT1-myasthenia reveals clinical, structural, and electrophysiologic heterogeneity (2013)
  • Author(s): Selcen D, Shen X-M, Milone M, Brengman J, Ohno K, McQuillen M, Deymeer F, Finkel R, Rowin J, Engel AG
  • Organizer: 65th American Academy of Neurology (Platform)
  • Place of Presentation: San Diego, USA
• [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)
• [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
• [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)
• [Book] "Collagen Q is a key player for developing rational therapy for congenital myasthenia and for dissecting the mechanisms of anti-MuSK myasthenia gravis" in J Mol Neurosci (2014)
  • Author(s): Ohno K, Ito M, Kawakami Y.
  • Publisher: Springer, New York
• [Book] "Molecular Genetics of Congenital Myasthenic Syndromes" in eLS (2014)
  • Author(s): Ohno K, Ohkawara B, Ito M, Engel AG.
  • Publisher: John Wiley & Sons, Inc., Hoboken
• [Book] "Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis." in Chem Biol Interact 203(1) (2013)
  • Author(s): Ohno K, Ito M, Kawakami Y, Krejci E, Engel AG.
  • Total Pages: 376
  • Publisher: Elsevier, Amsterdam