Comprehensive genetic analysis of Noonan syndrome and related disorders using next-generation sequencing(Fostering Joint International Research)

• Project/Area Number: 15KK0293
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Niihori Tetsuya 東北大学, 医学系研究科, 准教授 (40436134)
• Research Collaborator: Katsanis Nicholas Duke University Medical Center, Center for Human Disease Modeling, Professor ; Aoki Yoko ; Nagai Koki ; Davis Erica E.
• Project Period (FY): 2016 – 2018
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
• Keywords: ヌーナン症候群 / ゼブラフィッシュ / コステロ症候群 / CFC症候群 / RASopathies / 次世代シークエンサー / 遺伝子 / モデル動物

Outline of Final Research Achievements

We identified RRAS2 variants in patients with Noonan syndrome. We injected the wild-type or variant RNAs of RRAS2 into 1-4 cell-stage embryos. We measured the ceratohyal angle and body length of the larvae at 3 days post fertilization. The ceratohyal angles of larvae introduced with the variants were greater than that of wild-type. The body lengths of larvae with the variants were shorter than that of wild-type. These observations support the hypothesis that RRAS2 is a novel responsible gene of Noonan syndrome.

Academic Significance and Societal Importance of the Research Achievements

本研究はRRAS2の変異が先天性疾患であるヌーナン症候群の原因になることを世界で初めて明らかにするものである。ヌーナン症候群は指定難病および小児慢性特定疾病であり、診断基準上の「確実なヌーナン症候群」の診断は臨床症状より行われるが、判断が困難な場合がありうる。一方で「確定診断されたヌーナン症候群」は「上記確実なヌーナン症候群の要件を満たし、PTPN11などのRAS/MAPKシグナル伝達経路のヌーナン症候群責任遺伝子群に変異が同定された場合」とされており、RRAS2はヌーナン症候群責任遺伝子群の1つと考えられる。そのため、この発見は指定難病・小児慢性特定疾病と確定診断するために重要である。

Research Products

• [Int'l Joint Research] Duke大学(米国) (2016)
  • Year and Date: 2016-07-24
• [Journal Article] Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes (2018)
  • 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
  • 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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] Human genetic variation database, a reference database of genetic variations in the Japanese population. (2016)
  • Author(s): Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T, Migita O, (中略), Matsumoto N, Matsuda F.
  • Journal Title: J Hum Genet. Volume: advance online publication Issue: 6 Pages: 547-553
  • DOI: 10.1038/jhg.2016.12
  • Peer Reviewed / Open Access