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genetic analysis of causative factors for congenital scoliosis

Research Project

Project/Area Number 17K10986
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Orthopaedic surgery
Research InstitutionKeio University

Principal Investigator

WATANABE Kota  慶應義塾大学, 医学部(信濃町), 准教授 (60317170)

Co-Investigator(Kenkyū-buntansha) 武田 和樹  慶應義塾大学, 医学部(信濃町), 訪問研究員 (50594735)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords先天性側弯症 / 脊椎肋骨異形成症 / 全エクソン解析 / TBX6 / TBX6遺伝子 / 脊椎肋骨異骨症 / LFNG遺伝子 / 遺伝子 / 肋骨癒合を伴う先天性側弯症 / 脊柱側弯症 / エクソーム解析
Outline of Final Research Achievements

We investigated the novel causal genes of congenital scoliosis (CS) and spondylocostal dysostosis (SCDO) in 200 patients by next generation sequencing. We identified null mutations in TBX6 in 18 CS and one SCDO patients and novel missense mutations in LFNG in one CS patient. In vitro functional assays revealed that not only deleterious mutations (deletion, frame-shift and nonsense mutations) but also missense mutations had loss of function by decreased transcriptional activities, enzyme activities or mis-localization of proteins. Bi-allelic loss of function mutations in TBX6 and LFNG caused a spectrum of malformation of spine and rib including CS and SCDO according to the severity of the loss of function.

Academic Significance and Societal Importance of the Research Achievements

原因遺伝子とその遺伝様式が解明されれば、妊娠前の発症予測、出生後の進行予測が可能になる可能性がある。進行が予測される場合には、軽度の側弯症の段階で進行予防の低侵襲手術が可能になる。妊娠前の予測が可能になると、発症の可能性がない場合は、精神衛生上の問題も解決される。またCS発症進行予測モデル (キット) の製品化の可能性がある。本モデルは日本人だけでなく、中国人、アジア人、欧米人に対して適応できる可能性が高いため、製品はそれらの国々で使用される可能性がある。さらに、発症遺伝子の解明、進行遺伝子の同定により発症のメカニズムが解明されれば、創薬の開発等も現実になる可能性がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (19 results)

All 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (12 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results)

  • [Int'l Joint Research] Peking Union Medical Colleage Hospital(中国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Identification of novel LFNG mutations in spondylocostal dysostosis.2018

    • Author(s)
      Otomo N, Mizumoto S, Lu HF, Takeda K, Campos-Xavier B, Mittaz-Crettol L, Guo L, Takikawa K, Nakamura M, Yamada S, Matsumoto M, Watanabe K, Ikegawa S.
    • Journal Title

      Journal of human genetics

      Volume: - Issue: 3 Pages: 261-264

    • DOI

      10.1038/s10038-018-0548-2

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.2018

    • Author(s)
      Liu J, Wu N, Takeda K, Watanabe K, Matsumoto M, Qiu G.
    • Journal Title

      Genetics in Medicine

      Volume: - Issue: 7 Pages: 1548-1558

    • DOI

      10.1038/s41436-018-0377-x

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis.2018

    • Author(s)
      Otomo N, Takeda K, Kawai S, Kou I, Guo L, Osawa M, Alev C, Kawakami N, Miyake N, Matsumoto N, Yasuhiko Y, Kotani T, Suzuki T, Uno K, Sudo H, Inami S, Taneichi H, Shigematsu H, Watanabe K, Yonezawa I, Sugawara R, Taniguchi Y, Minami S, Kaneko K, Nakamura M, Matsumoto M, Toguchida J, Watanabe K, Ikegawa S.
    • Journal Title

      Journal of Medical Genetics

      Volume: - Issue: 9 Pages: 622-628

    • DOI

      10.1136/jmedgenet-2018-105920

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Screening of known disease genes in congenital scoliosis.2018

    • Author(s)
      Takeda K, Kou I, Mizumoto S, Yamada S, Kawakami N, Nakajima M, Otomo N, Ogura Y, Miyake N, Matsumoto N, Kotani T, Sudo H, Yonezawa I, Uno K, Taneichi H, Watanabe K, Shigematsu H, Sugawara R, Taniguchi Y, Minami S, Nakamura M, Matsumoto M; Japan Early Onset Scoliosis Research Group, Watanabe K, Ikegawa S.
    • Journal Title

      Molecular Genetics & Genomic Medicine

      Volume: - Issue: 6 Pages: 966-974

    • DOI

      10.1002/mgg3.466

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis.2017

    • Author(s)
      Takeda K, Kou I, Kawakami N, Iida A, Nakajima M, Ogura Y, Imagawa E, Miyake N, Matsumoto N, Yasuhiko Y, Sudo H, Kotani T, Japan Early Onset Scoliosis Research Group, Nakamura M, Matsumoto M, Watanabe K, Ikegawa S
    • Journal Title

      Human Mutation

      Volume: 38 Issue: 3 Pages: 317-323

    • DOI

      10.1002/humu.23168

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Response to Lefebvre et al.2017

    • Author(s)
      Takeda K, Kou I, Kawakami N, Yasuhiko Y, Ogura Y, Imagawa E, Miyake N, Matsumoto N, Sudo H, Kotani T, Japan Early Onset Scoliosis Research Group, Nakamura M, Matsumoto M, Watanabe K, Ikegawa S.
    • Journal Title

      Clinical Genetics

      Volume: 92 Issue: 5 Pages: 563-564

    • DOI

      10.1111/cge.13011

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 先天性側弯症および脊椎肋骨異形成症における TBX6 ミスセンス変異の病 因性の検討および患者の iPS 細胞を用いた検証2019

    • Author(s)
      大伴直央, 武田和樹, 川井俊介, 小倉洋二 川上紀明, 小谷俊明, 須藤英毅, 米澤郁穂, 宇野耕吉, 種市 洋, 渡辺 慶, 三宅紀子, 南 昌平, 重松英樹, 菅原 亮, 谷口優樹, 中村雅也, 松本守雄, 戸口田 淳也, 渡辺航太, 千葉一裕, 池川志郎
    • Organizer
      第48回 日本脊椎脊髄病学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] TBX6 ミスセンス変異は TBX6 蛋白質の細胞内局在異常を来し,先天性側弯症 および脊椎肋骨異形成症を引き起こす2019

    • Author(s)
      大伴直央, 武田和樹, 川井俊介, 小倉洋二, 川上紀明, 小谷俊明, 須藤英毅, 米澤郁穂, 宇野耕吉, 種市 洋, 渡辺 慶, 三宅紀子, 南 昌平, 重松英樹, 菅原 亮, 谷口優樹, 中村雅也, 松本守雄, 戸口田 淳也, 渡邉航太, 千葉一裕, 池川志郎
    • Organizer
      第92回日本整形外科学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] BX6 遺伝子の missense 変異は TBX6 の細胞内局在異常による機能の喪失により 先天性側弯症を引き起こす2018

    • Author(s)
      大伴直央, 武田和樹, 小倉洋二, 川上紀明, 小谷俊明, 須藤英毅, 米澤郁穂, 宇野耕吉, 種市 洋, 渡辺 慶, 三宅紀子, 南 昌平, 重松英樹, 菅原 亮, 谷口優樹, 中村雅也, 松本守雄, 渡邉航太, 千葉一裕, 池川志郎
    • Organizer
      第33回 日本整形外科学会基礎学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 先天性側弯症に対する遺伝子解析の現状2018

    • Author(s)
      武田和樹、黄郁代、小倉洋二、川上紀明、小谷俊明、須藤英毅、米澤郁穂、宇野耕吉、種市洋、渡辺慶、三宅紀子、南昌平、重松英樹、菅原亮、谷口優樹、中村雅也、松本守雄、渡辺航太、池川志郎
    • Organizer
      第33回 日本整形外科学会基礎学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 先天性側弯症の新規原因遺伝子の探索2018

    • Author(s)
      武田和樹、黄郁代、小倉洋二、川上紀明、小谷俊明、須藤英毅、米澤郁穂、宇野耕吉、種市洋、渡辺慶、三宅紀子、南昌平、重松英樹、菅原亮、谷口優樹、中村雅也、松本守雄、渡辺航太、池川志郎
    • Organizer
      第47回日本脊椎脊髄病学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Investigation for the novel genes of congenital scoliosis2018

    • Author(s)
      武田和樹、黄郁代、小倉洋二、川上紀明、小谷俊明、須藤英毅、米澤郁穂、宇野耕吉、種市洋、渡辺慶、三宅紀子、南昌平、重松英樹、菅原亮、谷口優樹、中村雅也、松本守雄、渡辺航太、池川志郎
    • Organizer
      第52回日本側弯症学会
    • Related Report
      2018 Research-status Report
  • [Presentation] TBX6遺伝子関連の先天性側弯症における表現型と遺伝型の関連性の検討2017

    • Author(s)
      武田和樹
    • Organizer
      第51回日本側弯症学会
    • Related Report
      2017 Research-status Report
  • [Presentation] TBX6遺伝子のnull mutationとhypomorphic risk haplotypeのcompound heterozygoteは先天性側弯症およびSpondylocostal dysostosisを引き起こす.2017

    • Author(s)
      武田和樹
    • Organizer
      第32回日本整形外科学会基礎学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 日本人におけるTBX6遺伝子関連の先天性側弯症の検討(続報).2017

    • Author(s)
      武田和樹
    • Organizer
      第46回日本脊椎脊髄病学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脊柱側弯症に対する遺伝子解析の現状2017

    • Author(s)
      武田和樹
    • Organizer
      第35回日本骨代謝学会学術集会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 脊柱側弯症に対する遺伝子解析の現状2017

    • Author(s)
      武田和樹
    • Organizer
      第28回日本小児整形外科学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Compound heterozygosity for null mutations and a common hypomorphic risk haplotype in TBX6 causes a spectrum of disorders from congenital scoliosis to spondylocostal dysostosis2017

    • Author(s)
      Kazuki Takeda
    • Organizer
      15th International Phillip Zorab Symposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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