Elucidation of molecular mechanisms of neuromuscular junction formations in physiology and pathology

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20H03561
• Research Institution: Nagoya University
• Principal Investigator: 大野 欽司 名古屋大学, 医学系研究科, 教授 (80397455)
• Co-Investigator(Kenkyū-buntansha): 増田 章男 名古屋大学, 医学系研究科, 准教授 (10343203) ; 大河原 美静 名古屋大学, 医学系研究科, 特任准教授 (80589606)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 神経筋接合部 / 先天性筋無力症候群

Outline of Annual Research Achievements

神経筋接合部(neuromuscular junction, NMJ)の正常分子構築機構を明らかにするとともに、先天性筋無力症候群(congenital myasthenic syndromes, CMS)の分子病態を解明し、新規治療法開発につなげることを研究目的とした2022年度末までに35種類の原因遺伝子が同定されてきた。研究代表者は、Rspo2, Fgf18, Ctgfの3種類の新規NMJ構築誘導細胞外分泌分子を同定し、それぞれの受容体(Lgr5, Fgfr2, Lrp4)との結合の機能解析により正常NMJ分子構築機構を明らかにしてきた。本邦DOK7-CMS患者から樹立したiPS細胞の解析を行いDOK7 PHドメインのp.G64R変異がprotein misfoldingによりproteasome系とautophagosome系に過剰な負荷を与えることにより核近傍にaggresomesを形成することを見出し論文報告した。加えて手指関節拘縮のみで翼状片を示さない本邦のEscobar症候群3例においてCHRNG p.P121T変異を同定し単一イオンチャンネル解析ならびにアセチルコリン受容体(AChR)イオンチャンネル動態解析によりp.P121Tは胎児型γ-AChRのファーストチャンネル症候群であることを明らかにし論文報告した。加えて442の文献を引用したCMSに関する大部の英文総説を執筆した。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model (2023)
  • Author(s): Kawashima Itaru、Matsushita Masaki、Mishima Kenichi、Kamiya Yasunari、Osawa Yusuke、Ohkawara Bisei、Ohno Kinji、Kitoh Hiroshi、Imagama Shiro
  • Journal Title: BMC Musculoskeletal Disorders Volume: 24 Pages: 200～200
  • DOI: 10.1186/s12891-023-06318-9
  • Peer Reviewed / Open Access
• [Journal Article] Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia (2023)
  • Author(s): Shen Xin‐Ming、Nakata Tomohiko、Mizuno Seiji、Imoto Issei、Selcen Duygu、Ohno Kinji、Engel Andrew G.
  • Journal Title: Annals of Clinical and Translational Neurology Volume: － Pages: －
  • DOI: 10.1002/acn3.51756
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Human-Induced Pluripotent Stem Cells Derived from a Patient with Schwartz-Jampel Syndrome Revealed Distinct Hyperexcitability in the Skeletal Muscles (2023)
  • Author(s): Yamashita Yuri、Nakada Satoshi、Nakamura Kyoko、Sakurai Hidetoshi、Ohno Kinji、Goto Tomohide、Mabuchi Yo、Akazawa Chihiro、Hattori Nobutaka、Arikawa-Hirasawa Eri
  • Journal Title: Biomedicines Volume: 11 Pages: 814～814
  • DOI: 10.3390/biomedicines11030814
  • Peer Reviewed / Open Access
• [Journal Article] Neural Isoforms of Agrin Are Generated by Reduced PTBP1-RNA Interaction Network Spanning the Neuron-Specific Splicing Regions in AGRN (2023)
  • Author(s): Bushra Samira、Lin Ying-Ni、Joudaki Atefeh、Ito Mikako、Ohkawara Bisei、Ohno Kinji、Masuda Akio
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Pages: 7420～7420
  • DOI: 10.3390/ijms24087420
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review (2023)
  • Author(s): Ohno Kinji、Ohkawara Bisei、Shen Xin-Ming、Selcen Duygu、Engel Andrew G.
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Pages: 3730～3730
  • DOI: 10.3390/ijms24043730
  • Peer Reviewed / Open Access
• [Journal Article] Promethazine Downregulates Wnt/β-Catenin Signaling and Increases the Biomechanical Forces of the Injured Achilles Tendon in the Early Stage of Healing (2022)
  • Author(s): Sakaguchi Takefumi、Ohkawara Bisei、Kishimoto Yasuzumi、Miyamoto Kentaro、Ishizuka Shinya、Hiraiwa Hideki、Ishiguro Naoki、Imagama Shiro、Ohno Kinji
  • Journal Title: The American Journal of Sports Medicine Volume: 50 Pages: 1317～1327
  • DOI: 10.1177/03635465221077116
  • Peer Reviewed
• [Journal Article] Meclozine ameliorates skeletal muscle pathology and increases muscle forces in mdx mice (2022)
  • Author(s): Kawamura Yusuke、Hida Tetsuro、Ohkawara Bisei、Matsushita Masaki、Kobayashi Takeshi、Ishizuka Shinya、Hiraiwa Hideki、Tanaka Satoshi、Tsushima Mikito、Nakashima Hiroaki、Ito Kenyu、Imagama Shiro、Ito Mikako、Masuda Akio、Ishiguro Naoki、Ohno Kinji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 592 Pages: 87～92
  • DOI: 10.1016/j.bbrc.2022.01.003
  • Peer Reviewed
• [Journal Article] Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase (2022)
  • Author(s): Koike Hiroshi、Nishida Yoshihiro、Shinomura Tamayuki、Ohkawara Bisei、Ohno Kinji、Zhuo Lisheng、Kimata Koji、Ushida Takahiro、Imagama Shiro
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 4089～4089
  • DOI: 10.3390/ijms23084089
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of auranofin as an inhibitor of desmoid progression (2022)
  • Author(s): Ito Kan、Nishida Yoshihiro、Hamada Shunsuke、Shimizu Koki、Sakai Tomohisa、Ohkawara Bisei、Alman Benjamin A.、Enomoto Atsushi、Ikuta Kunihiro、Koike Hiroshi、Zhang Jiarui、Ohno Kinji、Imagama Shiro
  • Journal Title: Scientific Reports Volume: 12 Pages: 11918～11918
  • DOI: 10.1038/s41598-022-15756-9
  • Peer Reviewed / Open Access
• [Journal Article] A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells (2022)
  • Author(s): Zhang Shaochuan、Ohkawara Bisei、Ito Mikako、Huang Zhizhou、Zhao Fei、Nakata Tomohiko、Takeuchi Tomoya、Sakurai Hidetoshi、Komaki Hirofumi、Kamon Masayoshi、Araki Toshiyuki、Ohno Kinji
  • Journal Title: Human Molecular Genetics Volume: 32 Pages: 1511～1523
  • DOI: 10.1093/hmg/ddac306
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of soluble lansoprazole-impregnated beta-tricalcium phosphate for bone regeneration (2022)
  • Author(s): Mishima Kenichi、Okabe Yuka Tsukagoshi、Mizuno Masaaki、Ohno Kinji、Kitoh Hiroshi、Imagama Shiro
  • Journal Title: Scientific Reports Volume: 12 Pages: 20550～20550
  • DOI: 10.1038/s41598-022-25184-4
  • Peer Reviewed / Open Access
• [Journal Article] Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X-linked hypophosphatemia (2022)
  • Author(s): Kamiya Yasunari、Matsushita Masaki、Mishima Kenichi、Ohkawara Bisei、Michigami Toshimi、Imagama Shiro、Ohno Kinji、Kitoh Hiroshi
  • Journal Title: Experimental and Therapeutic Medicine Volume: 25 Pages: 39～39
  • DOI: 10.3892/etm.2022.11738
  • Peer Reviewed / Open Access
• [Presentation] Meclozine ameliorates Fgf2-induced craniofacial bone hyperossification of larval zebrafish by attenuating MAPK pathway (2023)
  • Author(s): Takemoto G, Matsushita M, Ohno K, Imagama S.
  • Organizer: Orthopaedic Research Society 2023 Annual Meeting (Poster), Dallas, Texas, USA
  • Int'l Joint Research
• [Presentation] Three newly identified molecules that facilitate the formation of neuromuscular junction (2022)
  • Author(s): Ohno K
  • Organizer: XIIth International Symposium on Cholinergic Mechanisms, Dubrovnik, Croatia (hybrid)
  • Int'l Joint Research / Invited
• [Presentation] Updates on congenital myasthenic syndromes (2022)
  • Author(s): Ohno K
  • Organizer: 20th Asian Oceanian Myology Center Meeting, Jakarta, Indonesia (online)
  • Int'l Joint Research / Invited
• [Presentation] Painful muscle spasm with marked hyper-creatine kinase (CK) level after more than twenty weeks of four pregnant women with myotonic dystrophy type 1 (DM1) and a pregnant woman with paramyotonia congenita (PMC) (2022)
  • Author(s): Kinoshita M, Hara W, Yoshida N, Miyauchi A, Yamamoto M, Oji S, Fukaura H, Kaida K, Ohno K.
  • Organizer: 13th International Myotonic Dystrophy Consortium Meeting (Poster), Osaka, Japan
  • Int'l Joint Research
• [Presentation] Novel mutations at equivalent position in E-loops of AChR γ-and ε-subunits result in Escobar and congenital myasthenic syndrome respectively (2022)
  • Author(s): Shen XM, Nakata T, Mizuno S, Imoto I, Spilsbury PR, Swoboda KJ, Al-Mateen M, Selcen D, Ohno K, Engel AG.
  • Organizer: 147th American Neurology Association Annual Meeting (Poster), Chicago, IL
  • Int'l Joint Research
• [Presentation] Interactions between muscle glucose homeostasis and neuromuscular signal transduction - Lessons learned from lack of a muscle-specific long isoform of GFPT1 - (2022)
  • Author(s): Farshadyeganeh P, Nazim M, Ohkawara B, Masuda A, Ito M, Takeda J, Ohe K, Ohno K.
  • Organizer: European Human Genetics Conference 2022 (Platform), Vienna, Austria
  • Int'l Joint Research