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Functional analysis and modeling in RASopathies

Research Project

Project/Area Number 17H04223
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionTohoku University

Principal Investigator

Aoki Yoko  東北大学, 医学系研究科, 教授 (80332500)

Co-Investigator(Kenkyū-buntansha) 松原 洋一  国立研究開発法人国立成育医療研究センター, 所長室, 研究所長 (00209602)
新堀 哲也  東北大学, 医学系研究科, 准教授 (40436134)
井上 晋一  東北大学, 医学系研究科, 助教 (70622091)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywordsがん原遺伝子 / RAS / モデルマウス / Noonan症候群 / ゼブラフィッシュ / RAS/MAPKシグナル伝達経路 / 遺伝学 / シグナル伝達
Outline of Final Research Achievements

RASopathies are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the Ras/MAPK signaling pathway. In this project, w provided genetic analysis to patients with RASopathies and identified a novel gene, RRAS2, in Noonan syndrome patients (Niihori et al, Am J Hum Genet, 2019). Detailed clinical manifestations were evaluated in LZTR1 mutation-positive patients (Umeki I et al. Hum Mutat 2019). We demonstrated that LZTR1 associates with PPP1B-RAF1-SHOC2 complex. Although function in LZTR1 has not been clarified, we identified that LZTR1 facilitates polyubiquitination and degradation of RAS (Abe T et al. Cell Death Differ. 2020). We also showed that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction.

Academic Significance and Societal Importance of the Research Achievements

Noonan症候群は臨床症状のみで診断を付けることが困難な疾患であるので、その原因遺伝子を明らかにし、遺伝子診断提供により診療に貢献すると考えられる。LZTR1はNoonan症候群で遺伝子変異が同定されたもののその機能は全く明らかではなかった。研究代表者らが、LZTR1がPPP1CB,SHOC2と複合体を作ることを同定したことにより、初めてLZTR1がRAS/MAPKシグナル伝達経路に関与することをを示した報告である。さらにこれまでは全く明らかではなかったがん原遺伝子RASの分解制御機構にLZTR1が関与していることをが明らかになった。

Report

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

    (22 results)

All 2019 2018 2017 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 3 results) Presentation (11 results) (of which Int'l Joint Research: 5 results,  Invited: 6 results) Remarks (2 results)

  • [Journal Article] Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome2019

    • Author(s)
      Suzuki-Muromoto Sato、Miyabayashi Takuya、Nagai Koki、Yamamura-Suzuki Saeko、Anzai Mai、Takezawa Yusuke、Sato Ryo、Okubo Yukimune、Endo Wakaba、Inui Takehiko、Togashi Noriko、Kikuchi Atsuo、Niihori Tetsuya、Aoki Yoko、Kure Shigeo、Haginoya Kazuhiro
    • Journal Title

      Journal of Human Genetics

      Volume: 64 Issue: 5 Pages: 499-504

    • DOI

      10.1038/s10038-019-0579-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome2019

    • Author(s)
      Niihori Tetsuya、Nagai Koki、Fujita Atsushi、Ohashi Hirofumi、Okamoto Nobuhiko、Okada Satoshi、Harada Atsuko、Kihara Hirotaka、Arbogast Thomas、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Abe Taiki、Inoue Shin-ichi、Tsai I-Chun、Matsumoto Naomichi、Davis Erica E.、Katsanis Nicholas、Aoki Yoko
    • Journal Title

      The American Journal of Human Genetics

      Volume: 104 Issue: 6 Pages: 1233-1240

    • DOI

      10.1016/j.ajhg.2019.04.014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases2019

    • Author(s)
      Abe Taiki、Umeki Ikumi、Kanno Shin-ichiro、Inoue Shin-ichi、Niihori Tetsuya、Aoki Yoko
    • Journal Title

      Cell Death & Differentiation

      Volume: 27 Issue: 3 Pages: 1023-1035

    • DOI

      10.1038/s41418-019-0395-5

    • NAID

      130007898368

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes2018

    • Author(s)
      Umeki Ikumi、Niihori Tetsuya、Abe Taiki、Kanno Shin-ichiro、Okamoto Nobuhiko、Mizuno Seiji、Kurosawa Kenji、Nagasaki Keisuke、Yoshida Makoto、Ohashi Hirofumi、Inoue Shin-ichi、Matsubara Yoichi、Fujiwara Ikuma、Kure Shigeo、Aoki Yoko
    • Journal Title

      Human Genetics

      Volume: 138 Issue: 1 Pages: 21-35

    • DOI

      10.1007/s00439-018-1951-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death.2018

    • Author(s)
      Tamura A, Uemura S, Matsubara K, Kozuki E, Tanaka T, Nino N, Yokoi T, Saito A, Ishida T, Hasegawa D, Umeki I, Niihori T, Nakazawa Y, Koike K, Aoki Y, Kosaka Y.
    • Journal Title

      Clin Case Rep.

      Volume: 6 Issue: 7 Pages: 1202-1207

    • DOI

      10.1002/ccr3.1568

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis2018

    • Author(s)
      Oba Daiju、Inoue Shin-ichi、Miyagawa-Tomita Sachiko、Nakashima Yasumi、Niihori Tetsuya、Yamaguchi Seiji、Matsubara Yoichi、Aoki Yoko
    • Journal Title

      EBioMedicine

      Volume: 27 Pages: 138-150

    • DOI

      10.1016/j.ebiom.2017.11.029

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A patient with a novel purine-rich element binding protein A (PURA) mutation.2017

    • Author(s)
      Okamoto N, Nakao H, Niihori T, Aoki Y.
    • Journal Title

      Congenit Anom (Kyoto)

      Volume: 印刷中 Issue: 6 Pages: 201-204

    • DOI

      10.1111/cga.12214

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype.2017

    • Author(s)
      Ueda K, Yaoita M, Niihori T, Aoki Y, Okamoto N.
    • Journal Title

      Am J Med Genet A.

      Volume: 173 Issue: 9 Pages: 2346-2352

    • DOI

      10.1002/ajmg.a.38337

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice2017

    • Author(s)
      Inoue Shin-Ichi、Takahara Shingo、Yoshikawa Takeo、Niihori Tetsuya、Yanai Kazuhiko、Matsubara Yoichi、Aoki Yoko
    • Journal Title

      Hum Mol Genet

      Volume: 26 Issue: 23 Pages: 4715-4727

    • DOI

      10.1093/hmg/ddx354

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Noonan症候群類縁疾患の網羅的解析とLZTR1の機能解明2019

    • Author(s)
      青木洋子、梅木郁美、阿部太紀、岡本伸彦、水野誠司、黒澤健司、長崎啓祐、 吉田真、大橋博文、井上晋一, 松原洋一、藤原幾磨、呉繁夫、 新堀哲也
    • Organizer
      臨床遺伝2019 in Sapporo 第26回日本遺伝子診療学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Germline-Activationg RRAS2 mutations cause Noonan syndrome2019

    • Author(s)
      Niihori T, Nagai K, Fujita A, Ohashi H, Okamoto N, Okada S, Harada A, Kihara H, Arbogast T, Funayama R, Shirota M, Nakayama K, Abe T, Inoue SI, Tsai IC, Matsumoto N, Davis EE, Katsanis N, Aoki Y
    • Organizer
      6th International RASopathies Symposium:Precision Medicine : From Promise to Practice
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ZTR1 variants identified by genetic test for RASopathies using a targeted NGS panel.2019

    • Author(s)
      Nagai K, Umeki I, Katata Y, Inoue-Shibui , Abe T, Inoue S, Niihori T, Aoki Y.
    • Organizer
      6th International RASopathies Symposium:Precision Medicine; From Promise to Practice
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] RASopathies : genetic syndromes associated with the Ras/MAPK pathway2019

    • Author(s)
      Yoko Aoki, Shin-Ichi Inoue, Taiki Abe, Yu Katata, Aya Shibui-Inoue, Koki Nagai and Tetsuya Niihori
    • Organizer
      Tohoku Forum for Creativity Thematic program 2019 International symposium1 Cancer Etiology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] RASopathiesをめぐる最新の話題2019

    • Author(s)
      青木洋子
    • Organizer
      第37回日本染色体遺伝子学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The basis of nutritional and metabolic problems in RASopathies:Lessons form mouse models2018

    • Author(s)
      Shin-Ichi Inoue and Yoko Aoki
    • Organizer
      7th International Meeting on Rare Disorders of the RAS-MAPK Pathway
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathogenesis and treatment of esophageal dilation and gastric epithelial hyperplasia in a mouse model for cardio-facio-cutaneous syndrome2018

    • Author(s)
      Shin-ichi Inoue, Shingo Takahara, Takeo Yoshikawa, Kazuhiko Yanai, Yoichi Matsubara and Yoko Aoki
    • Organizer
      ESHG/EMPAG 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] RASopathies~新しい疾患概念とその病態解明~2018

    • Author(s)
      青木洋子
    • Organizer
      第42回日本小児皮膚科学会学術大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 単一遺伝子疾患におけるゲノム医療の発展:新しい疾患概念形成と治療法開発へ2017

    • Author(s)
      青木洋子
    • Organizer
      第60回日本腎臓学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 遺伝性疾患の病態解明から 新しい生命現象を明らかにする2017

    • Author(s)
      青木洋子
    • Organizer
      第59回日本小児神経学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] がん原遺伝 子Braf活性化はマウス食道の拡張、前胃上皮の過増殖をもたらす2017

    • Author(s)
      井上晋一、高原真吾、吉川雄朗、新堀哲也、谷内一彦、松原洋一、青木洋子
    • Organizer
      第40回分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Remarks] 東北大学大学院医学系研究科遺伝医療学分野研究室

    • URL

      http://www.medgen.med.tohoku.ac.jp/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 東北大学 大学院医学系研究科 遺伝医療学分野

    • URL

      http://www.medgen.med.tohoku.ac.jp/

    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2022-03-04  

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