Elucidation of pathogenesis of Noonan syndrome by novel causative gene LZTR1

• Project/Area Number: 18K15657
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tohoku University
• Principal Investigator: Abe Taiki 東北大学, 医学系研究科, 助教 (40810594)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: RASopathies / Noonan症候群 / ユビキチン・プロテアソーム経路 / LZTR1 / RAS/MAPK / RAS / ポリユビキチン修飾 / 遺伝学 / 先天奇形症候群 / RAS/MAPKシグナル伝達経路

Outline of Final Research Achievements

Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. LZTR1 is a causative gene of RASopathies, which are caused by germline mutations in genes encoding various components of the RAS/MAPK signaling pathway. However, no evidence regarding the functional interaction between LZTR1 and the RAS/MAPK signaling pathway had been reported.
In this study, we revealed that (1) LZTR1 regulates RAS/MAPK signal activity through the interaction of RAS and PPP1CB/SHOC2 /cRAF-complex, and (2) LZTR1 is involved in RAS degradation via the ubiquitin-proteasome pathway.

Academic Significance and Societal Importance of the Research Achievements

LZTR１はRASopahitesの原因分子であるとされていたもののRAS/MAPKシグナル伝達経路との関係は不明であった。そのため、治療法や治療薬の開発に際して治療標的分子を絞り込むことができず、各症状に対する対症療法以外に手立てがなかった。加えて、RASopathiesに分類される疾患は希少疾患であるためがんなどの大衆疾患に比べて研究開発が遅れている領域である。今回、LZTR1とRAS/MAPKシグナル伝達経路との関係が解明されたことで、治療薬開発における標的分子が明確となり、将来的な治療薬の開発が大いに期待される。

Research Products

• [Journal Article] LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] Noonan症候群原因遺伝子産物LZTR1によるRAS分解促進機構の解明 (2019)
  • Author(s): 阿部 太紀、梅木 郁美、菅野 新一郎、井上 晋一、新堀 哲也、青木 洋子
  • Organizer: 第42回日本分子生物学会
• [Presentation] Noonan症候群の原因遺伝子LZTR1―臨床的特徴と結合タンパクRAF1/PPP1CBの同定 (2019)
  • Author(s): 梅木郁美,新堀哲也,阿部太紀,長崎啓祐,井上晋一,藤原幾磨,呉繁夫,青木洋子
  • Organizer: 日本内分泌学会
• [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: 日本遺伝カウンセリング学会
• [Presentation] LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases (2019)
  • Author(s): Taiki Abe,Ikumi Umeki,Shin-ichiro Kanno,Shin-ichi Inoue,Tetsuya Niihori,Yoko Aoki
  • Organizer: Tohoku University Thematic Forum for Creativity Cancer from Biology to Acceptance
  • Int'l Joint Research