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The repeat expansion mechanism in Myotonic dystrophy type 1 patient-derived iPSCs.

Research Project

Project/Area Number 19K09565
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionEhime University (2020-2022)
National Center of Neurology and Psychiatry (2019)

Principal Investigator

Masayoshi Kamon  愛媛大学, 医学系研究科, 助教 (90557224)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords疾患iPS細胞 / DM1 / リピート病 / DNAミスマッチ修復 / iPS細胞
Outline of Research at the Start

I型筋強直性ジストロフィー(DM1)はリピート病の一つで、DMPK遺伝子の3’非翻訳領域に存在するCTGリピートが異常伸長することが原因である。最近の研究で、異常伸長したリピートがスプライシング異常を引き起こすことが明らかになってきているが、リピート自体がなぜ伸長するのかはよく分かっていない。そこで本研究では、DM1患者由来iPS細胞を用いたリピート伸長の細胞モデルでリピートが伸長するメカニズムの解明を行う。

Outline of Final Research Achievements

To analyze the mechanism of repeat instability, we established DM1 patient-derived iPS cells (DM1-iPSCs). We first isolated DM1-iPSC clones with different repeat sizes while they have identical genomic background. We happened to identify a DM1-iPSC clone whose repeat size was exceptionally stable even after long-term passages. Therefore, we performed comprehensive gene expression analysis to identify genes differentially regulated in the repeat expansion suppression clone. To identify whether any of differentially expressed genes may be related to the repeat stability of the repeat expansion suppression clone, we performed overexpression and down-regulation of each gene in DM1-iPSCs and examined the effect on repeat size. Furthermore, we revealed that the identified gene can associate with repeat sequences and colocalize with the DNA mismatch repair genes MSH2/MSH3.

Academic Significance and Societal Importance of the Research Achievements

疾患iPS細胞を用いた研究で治療薬開発の対象となる新遺伝子を同定することができた。同定した遺伝子はリピート配列に結合し、DNAミスマッチ修復(MMR)遺伝子と相互作用することが示唆されているため、本研究でMMR機構がリピートを異常伸長させるメカニズムの一端を明らかにしたとともに、DM1治療薬の対象として有望であることを示した。MMR遺伝子に作用する薬剤だとMMRが阻害される等の副作用が考えられるが、同定した遺伝子を対象にするとリピートの異常伸長に限定した効果が得られる可能性が高い。本研究によって、未だ有効な治療法のないDM1や他のリピート病に対する治療薬の開発に新たな可能性を示すことができた。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2022 2021 2020

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (5 results) (of which Int'l Joint Research: 2 results)

  • [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
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells.2020

    • Author(s)
      Huang K, Masuda A, Chen G, Bushra S, Kamon M, Araki T, Kinoshita M, Ohkawara B, Ito M, Ohno K
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 2558-2558

    • DOI

      10.1038/s41598-020-59517-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] WNTシグナルが引き起こすヒト羊膜上皮細胞分化過程における上皮間葉転換2021

    • Author(s)
      加門正義、加藤英政
    • Organizer
      2021年度分子生物学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 不死化ヒト結膜上皮細胞株(iHCjEC)を用いた杯細胞分化誘導条件の検討2021

    • Author(s)
      竹澤由起、加門正義、加門啓子、加藤英政、白石敦
    • Organizer
      2021年度分子生物学会
    • Related Report
      2021 Research-status Report
  • [Presentation] AMNION FORMATION IS THE FIRST EMT PROGRAM IN HUMAN DEVELOPMEN2021

    • Author(s)
      Masayoshi Kamon, Hidemasa Kato
    • Organizer
      ISSCR TOKYO Symposium, 2021
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] QUANTITATIVE DNA METHYLATION ANALYSIS OF BIVALENT DOMAINS ALLOWS SELECTING TUMOR-PRONE HUMAN IPS CELL CLONES2021

    • Author(s)
      Keiko Hiraki-Kamon, Makoto Motono, Masayoshi Kamon, Hideki Masaki, Ayaka Saito, Hidenori Kiyosawa, Yoichi Kondo and Hidemasa Kato
    • Organizer
      ISSCR, 2021
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒトiPS細胞由来の細胞を用いた神経筋接合部モデルの構築2020

    • Author(s)
      加門正義、若月修二、蕭淑麗(SIEW SOKELEE)、荒木敏之
    • Organizer
      第19回日本再生医療学会総会
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2025-01-30  

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