Epigenetic efects of the mutations in patients with the RAS/MAPK syndromes

• Project/Area Number: 23791148
• Research Category: Grant-in-Aid for Young Scientists (B)
• 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(研究院), 助教 (40436134)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 遺伝・先天異常学 / RAS/MAPK症候群 / RAS/MAPK / Noonan症候群 / Costello症候群 / CFC症候群 / 先天奇形症候群

Research Abstract

We identified a total of nine missense mutations in RIT1 gene, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome and related conditions without mutations in known genes. Clinical manifestations in the mutation-positive individuals are consistent with those of Noonan syndrome, which are characterized by distinctive facial appearance, short stature and congenital heart defects. Seventy percent of mutation-positive individuals had hypertrophic cardiomyopathy, a high frequency compared with the 20% incidence in individuals with Noonan syndrome overall.

Research Products

• [Journal Article] TBX1 Mutation Identified by Exome Sequencing in a Japanese Family with 22q11.2 Deletion Syndrome-like Craniofacial Features and Hypocalcemia. (2014)
  • Author(s): Ogata T*, Niihori T, Tanaka N, Kawai M, Nagashima T, Funayama R, Nakayama K, Nakashim S, Kato F, Fukami M, Aoki Y, Matsubara Y
  • Journal Title: PLoS One Volume: 9 Issue: 3 Pages: e91598-e91598
  • DOI: 10.1371/journal.pone.0091598
  • Peer Reviewed / Open Access
• [Journal Article] A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy (2014)
  • Author(s): Wakusawa K, Kobayashi S, Abe Y, Tanaka S, Endo W, Inui T, Iwaki M, Watanabe S, T ogashi N, Nara T, Niihori T, Aoki Y, Haginoya K
  • Journal Title: Brain Dev Volume: 36(1) Issue: 1 Pages: 61-63
  • DOI: 10.1016/j.braindev.2012.12.007
  • Peer Reviewed
• [Journal Article] Shimosegawa T . Sequential analysis of amino acid substitutions with hepatitis B virus in association with nucleoside/nucleotide analog treatment detected by deep sequencing (2014)
  • Author(s): Ninomiya M, Kondo Y, Niihori T, Nagashima T, Kogure T, Kakazu E, Kimura O, Aoki Y, Matsubara Y
  • Journal Title: Hepatol Res Volume: 44(6) Issue: 6 Pages: 678-684
  • DOI: 10.1111/hepr.12168
  • Peer Reviewed
• [Journal Article] Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome (2013)
  • Author(s): Aoki Y, Niihori T, Banio T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T Nakayama K, Inoue S, Watanabe Y, Oeura T, Matsubara Y
  • Journal Title: The American Journal of Human Genetics Volume: Volume 93, Issue 1 Issue: 1 Pages: 173-180
  • DOI: 10.1016/j.ajhg.2013.05.021
  • Peer Reviewed
• [Journal Article] Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure (2013)
  • Author(s): Izumi R, Niihori T, Aoki Y, Suzuki N, Kato M, Warita H, Takahashi T, Tateyama M, Nagashima T, Funayama R, Abe K, Nakayama K, Aoki M, Matsubara Y
  • Journal Title: J Hum Genet Volume: 58(5) Issue: 5 Pages: 259-66
  • DOI: 10.1038/jhg.2013.9
  • NAID: 10031177220
  • Peer Reviewed
• [Journal Article] Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan (2012)
  • Author(s): Abe Y, Aoki Y, Ogata T, et al
  • Journal Title: Am J Med Genet A Volume: (accepted)(Epub ahead of print) Issue: 5 Pages: 1083-1094
  • DOI: 10.1002/ajmg.a.35292
  • Peer Reviewed
• [Journal Article] Casitas B-cell lymphoma mutation in childhood T -cell acute lymphoblastic leukemia (2012)
  • Author(s): Saito Y, Aoki Y, Muramatsu H, Makishima H, Maciejewski JP, Imaizumi M, Rikiishi T, Sasahara Y, Kure S, Niihori T, Tsuchiya S, Kojima S, Matsubara Y
  • Journal Title: Leuk Res Volume: 36(8) Issue: 8 Pages: 1009-15
  • DOI: 10.1016/j.leukres.2012.04.018
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans (2012)
  • Author(s): Narisawa A
  • Journal Title: Hum Mol Genet Volume: 21 Issue: 7 Pages: 1496-1503
  • DOI: 10.1093/hmg/ddr585
  • Peer Reviewed
• [Journal Article] HRAS mutants identified in Costello syndrome patients can induce cellular senescence possible implications for the pathogenesis of Costello syndrome (2011)
  • Author(s): Niihori T, Ihara K, 他22名
  • Journal Title: Hum Genet Volume: 56(10) Issue: 10 Pages: 707-15
  • DOI: 10.1038/jhg.2011.85
  • NAID: 10030661239
  • Peer Reviewed
• [Journal Article] A familial case of LEOP ARD syndrome associated with a high-functioning autism spectrum disorder (2011)
  • Author(s): Watanabe Y, Yano S, Niihori T, Aoki Y, Matsubara Y, Yoshino M, Matsuishi T
  • Journal Title: Brain Dev Volume: 33(7) Issue: 7 Pages: 576-9
  • DOI: 10.1016/j.braindev.2010.10.006
  • NAID: 10031121955
  • Peer Reviewed
• [Presentation] エクソームシークエンスによるNoonan症候群新規原因遺伝子RIT1の同定 (2013)
  • Author(s): 新堀哲也、青木洋子、番匠俊博、岡本伸彦、水野誠司、黒澤健司、緒方勤、高田史男、長谷川奉延、舟山亮、長嶋剛史、中山啓子、井上晋一、渡邊裕介、小椋利彦、松原洋一
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
• [Presentation] Myofibrillar myopathyの大家系における次世代型シークエンサーを用いた新たな原因遺伝子の同定 (2013)
  • Author(s): 井泉瑠美子、新堀哲也、青木洋子、鈴木直輝、加藤昌昭、割田仁、高橋俊明、竪山真規、長嶋剛史、舟山亮、阿部康二、中山啓子、青木正志、松原洋一
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
• [Presentation] エクソーム解析によりTBX1変異が同定された家族性の特徴的顔貌・鼻咽頭閉鎖不全・低Ca血症を呈する5例 (2013)
  • Author(s): 緒方勤、田中紀子、河井昌彦、深見真紀、新堀哲也、青木洋子、松原洋一
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
• [Presentation] A mutation in A-band titin is associated with hereditary myopathy with early respiratory failure in a Japanese family (2013)
  • Author(s): R. Izumi, T. Niihori, Y. Aoki, N. Suzuki, M. Kato, H. Warita, T. Takahashi, M. Tateyama, T. Nagashima, R. Funayama, K. Abe, K. Nakayama, M. Aoki, Y. Matsubara
  • Organizer: American Society of Human Genetics 63rd Annual Meeting
  • Place of Presentation: 米国・ボストン
• [Presentation] Exome sequencing identifies mutations in a novel gene in patients with Noonan syndrome (2013)
  • Author(s): T. Niihori, Y. Aoki, T. Banjo, N. Okamoto, S. Mizuno, K. Kurosawa, T. Ogata, F. Takada, M. Yano, T. Ando, T. Hoshika, C. Barnett, H. Ohashi, H. Kawame, T. Hasegawa, T. Okutani, T. Nagashima, S. Hasegawa, R. Funayama, T. Nagashima, K. Nakayama, S. Inoue, Y. Watanabe, T. Ogura, Y. Matsubara
  • Organizer: American Society of Human Genetics 63rd Annual Meeting
  • Place of Presentation: 米国・ボストン
• [Presentation] エクソームシークエンスによるNoonan症候群新規原因遺伝子RIT1の同定 (2013)
  • Author(s): 新堀哲也、青木洋子、番匠俊博、岡本伸彦、 水野誠司、黒澤健司、緒方勤、高田史男、 長谷川奉延、舟山亮、長嶋剛史、中山啓子、 井上晋一、渡邊裕介、小椋利彦、松原洋一
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台市
• [Presentation] Exome sequencing identifies mutations in RIT1 in patients with Noonan syndrome (2013)
  • Author(s): T Niihori, Y Aoki, T Banjo, N Okamoto, S Mizuno, K Kurosawa, T Ogata, F Takada, M Yano, T Ando, T Hoshika, C Barnett, , H Ohashi, H Kawame, T Hasegawa, T Okutani, T Nagashima, S Hasegawa, R Funayama, T Nagashima, K Nakayama, SI Inoue, Y Watanabe, T Ogura, Y Matsubara
  • Organizer: 米国人類遺伝学会2013
  • Place of Presentation: ボストン（米国）
• [Presentation] 当分野におけるヌーナン症候群及び類縁疾患の遺伝子解析の現状 (2013)
  • Author(s): 新堀哲也、矢尾板全子、守谷充司、井泉瑠美子、大場大樹、西山亜由美、井上晋一、呉繁夫、 松原洋一、青木洋子
  • Organizer: 第216回日本小児科学会宮城地方会
  • Place of Presentation: 仙台市
• [Presentation] 東北大学病院遺伝科の現状 (2012)
  • Author(s): 飯倉 立夏、青木 洋子、新堀 哲也、小松崎 匠子、松原 洋一
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 東京
• [Presentation] コステロ症候群の遺伝子解析およびHRAS変異体の機能解析 (2011)
  • Author(s): 新堀哲也、青木洋子、阿部裕、斎藤由佳、小松崎匠子、松原洋一
  • Organizer: 第114回日本小児科学会学術集会
  • Place of Presentation: 東京
• [Presentation] コステロ症候群の遺伝子解析およびHRAS変異体の機能解析 (2011)
  • Author(s): 新堀哲也、青木洋子、岡本伸彦、黒澤健司、大橋博文、水野誠司、川目裕、松原洋一
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 千葉