Molecular analysis of congenital anomaly syndromes caused by intracellular signal transduction defects

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390268
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development (2013); Tohoku University (2011-2012)
• Principal Investigator: MATSUBARA Yoichi 独立行政法人国立成育医療研究センター, その他部局等, その他 (00209602)
• Co-Investigator(Kenkyū-buntansha): 新堀 哲也 東北大学 (40436134) ; 呉 繁夫 東北大学 (10205221)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 遺伝性疾患 / 細胞内シグナル伝達 / 遺伝子変異

Research Abstract

We identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals with Noonan syndrome. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidencein individuals with Noonan syndrome. These RIT1 alterations enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

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, Nakashima S, Kato F, Fukami M, Aoki Y, Matsubara Y
  • Journal Title: PLoS One Volume: 9(3) Pages: e91598
  • DOI: 10.1371/journal.pone.0091598
  • Peer Reviewed
• [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) Pages: 36(1)
  • DOI: 10.1016/j.braindev.2012.12.007
  • Peer Reviewed
• [Journal Article] Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213 : a susceptibility gene for moyamoya disease (2014)
  • Author(s): Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, Kikuchi A, Arai-Ichinoi N, Kure S, T ominaga T
  • Journal Title: Brain Res Volume: 1552 Pages: 64-71
  • DOI: 10.1016/j.brainres.2014.01.011.Epub2014Jan17
  • 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) Pages: 678-684
  • DOI: 10.1111/hepr.12168
  • Peer Reviewed
• [Journal Article] RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy (2014)
  • Author(s): Nakayama T, Saitsu H, Endo W, Kikuchi A, Uematsu M, Haginoya K, Hino-Fukuyo N, Kobayashi T, Iwasaki M, T ominaga T, Kure S, Matsumoto N
  • Journal Title: Brain Dev Volume: 36(6) Pages: 532-6
  • DOI: 10.1016/j.braindev.2013.07.009.Epub2013Aug16
  • 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, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Y ano 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, Ogura T, Matsubara Y
  • Journal Title: Am J Hum Genet Volume: 93(1) Pages: 173-80
  • 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) Pages: 259-66
  • DOI: 10.1038/jhg.2013.9
  • Peer Reviewed
• [Journal Article] Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations (2013)
  • Author(s): Kitazawa H, Moriya K, Niizuma H, Kawano K, Saito-Nanjo Y, Uchiyama T, Rikiishi T, Sasahara Y, Sakamoto O, Setoguchi Y, Kure S
  • Journal Title: Eur J Pediatr Volume: 172(7) Pages: 953-7
  • DOI: 10.1007/s00431-013-1977-8.Epub2013Feb27
  • 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) Pages: 1009-15
  • DOI: 10.1016/j.leukres.2012.04.018
  • Peer Reviewed
• [Journal Article] Costello and CFC syndrome study group in Japan. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan : findings from a nationwide epidemiological survey (2012)
  • Author(s): Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Ogata T, Kure S, Niihori T, Matsubara Y
  • Journal Title: Am J Med Genet A Volume: 158A(5) Pages: 1083-94
  • DOI: 10.1002/ajmg.a.35292
  • 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, Komatsuzaki S, Kikuchi A, Niihori T, Aoki Y, Fujiwara K, Tanemura M, Hata A, Suzuki Y, Relton CL, Grinham J, Leung KY, Partridge D, Robinson A, Stone V, Gustavsson P, Stanier P, Copp AJ, Greene ND, T ominaga T, Matsubara Y, Kure S
  • Journal Title: Hum Mol Genet Volume: 21(7) Pages: 1496-503
  • DOI: 10.1093/hmg/ddr585
  • Peer Reviewed
• [Journal Article] Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease (2012)
  • Author(s): Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, Tsurusaki Y, Doi H, Sakai H, Saitsu H, Shimojima K, Y amamoto T, Higurashi M, Kawahara N, Kawauchi H, Nagasaka K, Okamoto N, Mori T, Koyano S, Kuroiwa Y, Taguri M, Morita S, Matsubara Y, Kure S, Matsumoto N
  • Journal Title: Neurology Volume: 78(11) Pages: 803-10
  • DOI: 10.1212/WNL.0b013e318249f71f.Epub2012Feb29
  • Peer Reviewed
• [Journal Article] Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13 (2012)
  • Author(s): Kikuchi A, Arai-Ichinoi N, Sakamoto O, Matsubara Y, Saheki T, Kobayashi K, Ohura T, Kure S
  • Journal Title: Mol Genet Metab Volume: 105(4) Pages: 553-8
  • DOI: 10.1016/j.ymgme.2011.12.024.Epub2012Jan8
  • 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, Aoki Y, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Kawame H, Inazawa J, Ohura T, Arai H, Nabatame S, Kikuchi K, Kuroki Y, Miura M, Tanaka T, Ohtake A, Omori I, Ihara K, Mabe H, Watanabe K, Niijima S, Okano E, Numabe H, Matsubara Y
  • Journal Title: J Hum Genet Volume: 56(10) Pages: 707-15
  • DOI: 10.1038/jhg.2011.85
  • 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) Pages: 576-9
  • DOI: 10.1016/j.braindev.2010.10.006
  • 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
  • Year and Date: 20131120-23
• [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
  • Year and Date: 20131120-23
• [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
  • Year and Date: 20131120-23
• [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
  • Year and Date: 20131120-23
• [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. Y ano, 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
  • Year and Date: 20131120-23
• [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
  • Year and Date: 20121025-27
• [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
  • Year and Date: 20111109-12