Functional analysis and modeling in RASopathies
| Project/Area Number |
17H04223
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tohoku University |
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Principal Investigator |
Aoki Yoko 東北大学, 医学系研究科, 教授 (80332500)
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| 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)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| 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)
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| 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 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(22 results)
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[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
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Journal Title
The American Journal of Human Genetics
Volume: 104
Pages: 1233-1240
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Clin Case Rep.
Volume: 6
Pages: 1202-1207
DOI
Related Report
Peer Reviewed
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[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
Int'l Joint Research
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