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Pathological analysis of limb girdle congenital myasthenia and development of new therapy

Research Project

Project/Area Number 20K06925
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 46030:Function of nervous system-related
Research InstitutionNagoya University

Principal Investigator

Ito Mikako  名古屋大学, 医学系研究科, 講師 (60444402)

Co-Investigator(Kenkyū-buntansha) 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 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords先天性筋無力症候群 / GFPT1 / 神経筋接合部 / DOK7 / 先天性筋無力症行群
Outline of Research at the Start

先天的な神経筋接合部の分子欠損による先天性筋無力症候群 (congenital myasthenic syndromes, CMS)の原因として30種類の分子が報告されており、筋力低下や易疲労性を呈し、軽度から重度の呼吸困難、嚥下困難、四肢筋力低下が認められる。本研究では、CMS患者と同じ変異を持つマウスを作製し、神経筋接合部での病態機構解析を行う。またCMS患者由来iPS細胞を用いたGFPT1, DOK7の遺伝子変異の機能解析を行い、既認可薬からスクリーニングによる新規治療法の開発に取り組む。

Outline of Final Research Achievements

Congenital myasthenia syndrome (CMS) is caused by a mutation in GFPT1 (Glutamine fructose-6-phosphate aminotransferase 1), a protein and lipid glycosylase, characterized by limb-girdle type muscle weakness. To investigate the role of the GFPT1-L variant in skeletal muscle, Gfpt1-L-/- mice, which do not express GFPT1-L, were created, and these mice showed muscle weakness in old age. Gfpt1 knock-in (KI) mice were also created by introducing the c.722r3insG mutation into mice as in CMS patients. They showed a phenotype similar to that of patients, including reduced motor function, reduced amounts of glycosylated proteins, fragmentation of AChR clusters, muscle atrophy and increased inter-myofibrillar space, and observed reduced motor performance and abnormal neuromuscular junction structures with ageing.

Academic Significance and Societal Importance of the Research Achievements

先天性筋無力症候群は指定難病の対象となっており、全身の筋力低下, 易疲労性を呈し,生後 1 年以内に発症することが多い稀な疾患である。神経筋接合部を構成する遺伝子検査を実施し、変異が発見された場合は、CMSの原因となりうる変異かどうかを精査する必要がある。本研究では先天性筋無力症候群患者において、GFPT1内に複合ヘテロ変異を同定し、同じ変異を有するマウスを作成して病態の詳細な解析を行い、骨格筋において不適応な小胞体ストレス応答によりタンパク質凝集体が除去されずアポトーシスを引き起こしていることが明らかになった。今後、治療薬のスクリーニング、治療法の開発へ応用できると期待している。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (29 results)

All 2024 2023 2022 2021 2020 Other

All Journal Article (24 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 24 results,  Open Access: 21 results) Presentation (3 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] Extremely Low Frequency, Extremely Low Magnetic Environment for depression: An open-label trial2024

    • Author(s)
      Tachibana Masako、Inada Toshiya、Kimura Hiroki、Ito Mikako、Kuwatsuka Yachiyo、Kinoshita Fumie、Mori Daisuke、Ohno Kinji
    • Journal Title

      Asian Journal of Psychiatry

      Volume: 96 Pages: 104036-104036

    • DOI

      10.1016/j.ajp.2024.104036

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo22024

    • Author(s)
      Ohkawara Bisei、Tomita Hiroyuki、Inoue Taro、Zhang Shaochuan、Kanbara Shunsuke、Koshimizu Hiroyuki、Miyasaka Yuki、Takeda Jun-ichi、Nishiwaki Hiroshi、Nakashima Hiroaki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Ogi Tomoo、Ohno Tamio、Imagama Shiro、Ohno Kinji
    • Journal Title

      Neurotherapeutics

      Volume: 21 Issue: 2 Pages: e00318-e00318

    • DOI

      10.1016/j.neurot.2024.e00318

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Splicing regulation of GFPT1 muscle-specific isoform and its roles in glucose metabolisms and neuromuscular junction2023

    • Author(s)
      Farshadyeganeh Paniz、Nazim Mohammad、Zhang Ruchen、Ohkawara Bisei、Nakajima Kazuki、Rahman Mohammad Alinoor、Nasrin Farhana、Ito Mikako、Takeda Jun-ichi、Ohe Kenji、Miyasaka Yuki、Ohno Tamio、Masuda Akio、Ohno Kinji
    • Journal Title

      iScience

      Volume: 26 Issue: 10 Pages: 107746-107746

    • DOI

      10.1016/j.isci.2023.107746

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Extremely low-frequency electromagnetic field induces acetylation of heat shock proteins and enhances protein folding2023

    • Author(s)
      Huang Zhizhou、Ito Mikako、Zhang Shaochuan、Toda Takuro、Takeda Jun-ichi、Ogi Tomoo、Ohno Kinji
    • Journal Title

      Ecotoxicology and Environmental Safety

      Volume: 264 Pages: 115482-115482

    • DOI

      10.1016/j.ecoenv.2023.115482

    • Related Report
      2023 Annual Research Report
    • 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 AGRN2023

    • 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 Issue: 8 Pages: 7420-7420

    • DOI

      10.3390/ijms24087420

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts.2023

    • Author(s)
      Muraoka Ayako、Suzuki Miho、Hamaguchi Tomonari、Watanabe Shinya、Iijima Kenta、Murofushi Yoshiteru、Shinjo Keiko、Osuka Satoko、Hariyama Yumi、Ito Mikako、Ohno Kinji、Kiyono Tohru、Kyo Satoru、Iwase Akira、Kikkawa Fumitaka、Kajiyama Hiroaki、Kondo Yutaka.
    • Journal Title

      Science Translational Medicine

      Volume: 15 Issue: 700 Pages: 700-700

    • DOI

      10.1126/scitranslmed.add1531

    • Related Report
      2023 Annual Research Report
    • 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 cells2022

    • 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 Issue: 9 Pages: 1511-1523

    • DOI

      10.1093/hmg/ddac306

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of Pesticide Intake on Gut Microbiota and Metabolites in Healthy Adults2022

    • Author(s)
      Ueyama Jun、Hayashi Mai、Hirayama Masaaki、Nishiwaki Hiroshi、Ito Mikako、Saito Isao、Tsuboi Yoshio、Isobe Tomohiko、Ohno Kinji
    • Journal Title

      International Journal of Environmental Research and Public Health

      Volume: 20 Issue: 1 Pages: 213-213

    • DOI

      10.3390/ijerph20010213

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short chain fatty acids-producing and mucin-degrading intestinal bacteria predict the progression of early Parkinson’s disease2022

    • Author(s)
      Nishiwaki Hiroshi、Ito Mikako、Hamaguchi Tomonari、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Yoshida Takumi、Hanada Hiroyuki、Takeuchi Ichiro、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      npj Parkinson's Disease

      Volume: 8 Issue: 1 Pages: 65-65

    • DOI

      10.1038/s41531-022-00328-5

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gut microbiota in dementia with Lewy bodies2022

    • Author(s)
      Nishiwaki Hiroshi、Ueyama Jun、Kashihara Kenichi、Ito Mikako、Hamaguchi Tomonari、Maeda Tetsuya、Tsuboi Yoshio、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      npj Parkinson's Disease

      Volume: 8 Issue: 1 Pages: 169-169

    • DOI

      10.1038/s41531-022-00428-2

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis2022

    • Author(s)
      Gibo Noriaki、Hamaguchi Tomonari、Miki Yasuo、Yamamura Takeshi、Nakaguro Masato、Ito Mikako、Nakamuara Masanao、Kawashima Hiroki、Hirayama Masaaki、Hirooka Yoshiki、Wakabayashi Koichi、Ohno Kinji
    • Journal Title

      Journal of Gastrointestinal and Liver Diseases

      Volume: 31 Issue: 3 Pages: 290-300

    • DOI

      10.15403/jgld-4313

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria2022

    • Author(s)
      Toda Takuro、Ito Mikako、Takeda Jun-ichi、Masuda Akio、Mino Hiroyuki、Hattori Nobutaka、Mohri Kaneo、Ohno Kinji
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 453-453

    • DOI

      10.1038/s42003-022-03389-7

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response2022

    • Author(s)
      Hasegawa Tomoya、Ito Mikako、Hasegawa Satoru、Teranishi Masaki、Takeda Koki、Negishi Shuto、Nishiwaki Hiroshi、Takeda Jun-ichi、LeBaron Tyler W.、Ohno Kinji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 5 Pages: 2888-2888

    • DOI

      10.3390/ijms23052888

    • Related Report
      2022 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Altered gut microbiota in Parkinson's disease patients with motor complications2022

    • Author(s)
      Takahashi Kai、Nishiwaki Hiroshi、Ito Mikako、Iwaoka Kazuhiro、Takahashi Kenta、Suzuki Yoshio、Taguchi Keita、Yamahara Kanako、Tsuboi Yoshio、Kashihara Kenichi、Hirayama Masaaki、Ohno Kinji、Maeda Tetsuya
    • Journal Title

      Parkinsonism & Related Disorders

      Volume: 95 Pages: 11-17

    • DOI

      10.1016/j.parkreldis.2021.12.012

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma2021

    • Author(s)
      Tanaka Hiromasa、Matsumura Shogo、Ishikawa Kenji、Hashizume Hiroshi、Ito Masafumi、Nakamura Kae、Kajiyama Hiroaki、Kikkawa Fumitaka、Ito Mikako、Ohno Kinji、Okazaki Yasumasa、Toyokuni Shinya、Mizuno Masaaki、Hori Masaru
    • Journal Title

      Japanese Journal of Applied Physics

      Volume: 61 Issue: SA Pages: SA1007-SA1007

    • DOI

      10.35848/1347-4065/ac2037

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Plasma‐activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells2021

    • Author(s)
      Tanaka Hiromasa、Maeda Shogo、Nakamura Kae、Hashizume Hiroshi、Ishikawa Kenji、Ito Mikako、Ohno Kinji、Mizuno Masaaki、Motooka Yashiro、Okazaki Yasumasa、Toyokuni Shinya、Kajiyama Hiroaki、Kikkawa Fumitaka、Hori Masaru
    • Journal Title

      Plasma Processes and Polymers

      Volume: 18 Issue: 10 Pages: 2100056-2100056

    • DOI

      10.1002/ppap.202100056

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulated splicing of large exons is linked to phase‐separation of vertebrate transcription factors2021

    • Author(s)
      Kawachi Toshihiko、Masuda Akio、Yamashita Yoshihiro、Takeda Jun‐ichi、Ohkawara Bisei、Ito Mikako、Ohno Kinji
    • Journal Title

      The EMBO Journal

      Volume: 40 Issue: 22

    • DOI

      10.15252/embj.2020107485

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intestinal Collinsella may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate2021

    • Author(s)
      Hirayama Masaaki、Nishiwaki Hiroshi、Hamaguchi Tomonari、Ito Mikako、Ueyama Jun、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ohno Kinji
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 11 Pages: 0260451-0260451

    • DOI

      10.1371/journal.pone.0260451

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson’s Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder2020

    • Author(s)
      Nishiwaki Hiroshi、Hamaguchi Tomonari、Ito Mikako、Ishida Tomohiro、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      mSystems

      Volume: 5 Issue: 6

    • DOI

      10.1128/msystems.00797-20

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage2020

    • Author(s)
      Takeuchi Akihide、Takahashi Yuji、Iida Kei、Hosokawa Motoyasu、Irie Koichiro、Ito Mikako、Brown J.B.、Ohno Kinji、Nakashima Kinichi、Hagiwara Masatoshi
    • Journal Title

      Stem Cell Reports

      Volume: 15 Issue: 4 Pages: 883-897

    • DOI

      10.1016/j.stemcr.2020.08.010

    • NAID

      120006888017

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle2020

    • Author(s)
      Huang Kun、Li Jin、Ito Mikako、Takeda Jun-Ichi、Ohkawara Bisei、Ogi Tomoo、Masuda Akio、Ohno Kinji
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 13 Pages: 154-154

    • DOI

      10.3389/fnmol.2020.00154

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model2020

    • Author(s)
      Koshimizu Hiroyuki、Ohkawara Bisei、Nakashima Hiroaki、Ota Kyotaro、Kanbara Shunsuke、Inoue Taro、Tomita Hiroyuki、Sayo Akira、Kiryu-Seo Sumiko、Konishi Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Kiyama Hiroshi、Ohno Kinji
    • Journal Title

      Life Sciences

      Volume: 263 Pages: 118577-118577

    • DOI

      10.1016/j.lfs.2020.118577

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Meta‐Analysis of Gut Dysbiosis in Parkinson's Disease2020

    • Author(s)
      Nishiwaki Hiroshi、Ito Mikako、Ishida Tomohiro、Hamaguchi Tomonari、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      Movement Disorders

      Volume: 35 Issue: 9 Pages: 1626-1635

    • DOI

      10.1002/mds.28119

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] tRIP-seq Reveals Repression of Premature Polyadenylation by Co-Transcriptional FUS-U1 snRNP Assembly2020

    • Author(s)
      Akio Masuda, Toshihiko Kawachi, Jun-Ichi Takeda, Bisei Ohkawara, Mikako Ito, Kinji Ohno
    • Journal Title

      EMBO Rep.

      Volume: - Issue: 5

    • DOI

      10.15252/embr.201949890

    • NAID

      120006884959

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 分子状水素はSirt3を増加させミトコンドリア機能を向上させる2022

    • Author(s)
      伊藤美佳子,大野欽司
    • Organizer
      第11 回分子状水素医学生物学会
    • Related Report
      2022 Research-status Report
  • [Presentation] 超微弱パルス磁場はマイトファジーを誘導しミトコンドリアを活性化する2022

    • Author(s)
      伊藤 美佳子, 戸田 拓郎, 三野 広幸, 毛利 佳年雄, 大野 欽司
    • Organizer
      第95回 日本生化学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 速筋の神経筋接合部終板における網羅的遺伝子発現解析2021

    • Author(s)
      伊藤美佳子、Kun Huang、大野欽司
    • Organizer
      第7回日本筋学会
    • Related Report
      2021 Research-status Report
  • [Remarks] 名古屋大学大学院医学系研究科 神経遺伝情報学

    • URL

      https://www.med.nagoya-u.ac.jp/medical_J/laboratory/basic-med/advanced-med/neurogenetics/

    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 磁場発生装置および磁場照射方法2021

    • Inventor(s)
      大野 欽司
    • Industrial Property Rights Holder
      東海国立大学機構
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report
    • Overseas

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

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