Molecular analysis and pathogenesis of the RAS/MAPK syndromes

• Project/Area Number: 26293241
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学(系)研究科(研究院), 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, 研究所, 研究所長 (00209602) ; 新堀 哲也 東北大学, 医学(系)研究科(研究院), 准教授 (40436134) ; 井上 晋一 東北大学, 医学(系)研究科(研究院), 助教 (70622091)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 遺伝性疾患 / シークエンス / モデルマウス / 先天異常症 / 肥大型心筋症 / 遺伝子診断 / 遺伝学 / シグナル伝達 / 遺伝子 / ヌーナン症候群 / RAS

Outline of Final Research Achievements

We have performed genetic testing in patients with RASopathies and successfully identified a new gene, RIT1, in patients with Noonan syndrome. In this study, we further analyzed clinical manifestations in RIT1 mutation-positive patients and performed functional analysis in cell culture system. We developed comprehensive analysis system using a next generation sequencer to analyze genes for RASopathies. We successfully generated model mice for CFC syndrome. The results would lead to the understanding of the pathogenesis of these disorders and the development of therapeutic means.

Research Products

• [Int'l Joint Research] La Paz University Hospital, Madrid(スペイン)
• [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] Recent advances in RASopathies. (2016)
  • Author(s): Aoki Y, Niihori T, Inoue S, Matsubara Y.
  • Journal Title: J Hum Genet. Volume: 61 Issue: 1 Pages: 33-39
  • DOI: 10.1038/jhg.2015.114
  • NAID: 40020859216
  • Peer Reviewed
• [Journal Article] Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. (2016)
  • Author(s): Yaoita M, Niihori T, Mizuno S, Okamoto N, Hayashi S, Watanabe A, Yokozawa M, Suzumura H, Nakahara A, Nakano Y, Hokosaki T, Ohmori A, Sawada H, Migita O, Mima A, Lapunzina P, Santos-Simarro F, García-Miñaúr S, Ogata T, Kawame H, Kurosawa K, Ohashi H, Inoue S, Matsubara Y, Kure S, Aoki Y.
  • Journal Title: Hum Genet. Volume: 135 Issue: 2 Pages: 209-222
  • DOI: 10.1007/s00439-015-1627-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype. (2015)
  • Author(s): Moriya M, Inoue S, Miyagawa-Tomita S, Nakashima Y, Oba D, Niihori T, Hashi M, Ohnishi H, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 25 Pages: 7349-7360
  • DOI: 10.1093/hmg/ddv435
  • Peer Reviewed
• [Journal Article] A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. (2015)
  • Author(s): Nishi E, Mizuno S, Nanjo Y, Niihori T, Fukushima Y, Matsubara Y, Aoki Y, Kosho T.
  • Journal Title: Am J Med Genet A. Volume: 167 Issue: 2 Pages: 407-411
  • DOI: 10.1002/ajmg.a.36842
  • Peer Reviewed
• [Journal Article] New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. (2014)
  • Author(s): Inoue S. I. et al.
  • Journal Title: Hum. Mol. Genet. Volume: 23 Issue: 24 Pages: 6553-6566
  • DOI: 10.1093/hmg/ddu376
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. (2014)
  • Author(s): Flex E , (33人）、Aoki Y, Loh ML, Palleschi A, Di Schiavi E, Carè A, Selicorni A, Dallapiccola B, Cirstea IC, Stella L, Zenker M, Gelb BD, Cavé H, Ahmadian MR, Tartaglia M.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 16 Pages: 4315-4327
  • DOI: 10.1093/hmg/ddu148
  • Peer Reviewed
• [Presentation] ヌーナン症候群類縁疾患におけるRIT1遺伝子解析と臨床的特徴の検討 (2016)
  • Author(s): 矢尾板全子、大場大樹、梅木郁美、水野誠司、岡本伸彦、井上晋一、松原洋一、呉繁夫、新堀哲也、青木洋子
  • Organizer: 第119回日本小児科学会学術集会
  • Place of Presentation: 札幌 （ロイトン札幌）
  • Year and Date: 2016-05-13
• [Presentation] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype (2016)
  • Author(s): Inoue S, Moriya M, Miyagawa-Tomita S, Nakashima Y, Oba D, Niihori T, Hashi M, Ohnishi H, Kure S, Matsubara Y, Aoki Y
  • Organizer: ICHG 2016 The 13th International Congress of Human Genetics
  • Place of Presentation: 京都 （国立京都国際会館）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] RASopathies: 広がりゆく疾患概念 (2016)
  • Author(s): 青木洋子
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都 （国立京都国際会館）
  • Invited
• [Presentation] RASopathies: genetic syndromes associated with the Ras/MAPK pathway (2016)
  • Author(s): Yoko Aoki
  • Organizer: 日本研究皮膚科学会 第41回年次学術大会・総会
  • Place of Presentation: 仙台 （仙台国際センター）
  • Invited
• [Presentation] Noonan症候群と類縁疾患における遺伝子診断体制の確立とその病態解明 (2016)
  • Author(s): 青木洋子、梅木郁美、大場大樹、西山亜由美、矢尾板全子、井上晋一、松原洋一、新堀哲也
  • Organizer: 第23回 日本遺伝子診療学会大会
  • Place of Presentation: 東京 （イイノホール＆カンファレンスセンター）
• [Presentation] 遺伝病と血液疾患 (2015)
  • Author(s): 青木洋子
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢（ホテル金沢）
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] BRAF knock-in mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in RASopathies (2015)
  • Author(s): Shin-ichi Inoue, Mitsuji Moriya, Tetsuya Niihori, Daiju Oba, Yoichi Matsubara and Yoko Aoki
  • Organizer: 4th international RASopathies symposium
  • Place of Presentation: シアトル、アメリカ (Doubletree at Seattle-Tacoma International Airport)
  • Year and Date: 2015-07-17
  • Int'l Joint Research
• [Presentation] Cardio-facio-cutaneous症候群のモデルマウス作製とその病態解析 (2015)
  • Author(s): 青木洋子、井上晋一、守谷充司、大場大樹、新堀哲也、呉繁夫、松原洋一
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: （大阪国際会議場 / リーガロイヤルホテル大阪）
  • Year and Date: 2015-04-17
• [Presentation] BRAF knock-in mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in RASopathies (2014)
  • Author(s): 井上晋一、守谷充司、渡邉裕介、宮川－富田幸子、新堀哲也、大場大樹、小野栄夫、呉繁夫、小椋利彦、松原洋一、青木洋子
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 次世代シークエンサーを用いた希少遺伝性疾患の遺伝子解析研究の現状 (2014)
  • Author(s): 青木洋子
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: 東京、タワーホール船橋
  • Year and Date: 2014-11-19 – 2014-11-22
  • Invited
• [Presentation] ヌーナン症候群の新規原因遺伝子RIT1の同定 (2014)
  • Author(s): 青木洋子、新堀哲也、岡本伸彦、水野誠司、黒澤健司、緒方勤、井上晋一、松原洋一
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋、名古屋国際会議場
  • Year and Date: 2014-04-11 – 2014-04-13
• [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/
• [Remarks] 東北大学・大学院医学系研究科・遺伝病学分野
  • URL: http://www.medgen.med.tohoku.ac.jp/