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

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2011: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 遺伝性疾患 / 細胞内シグナル伝達 / 遺伝子変異 / i遺伝子 / シグナル伝達 / 遺伝子診断 / Ras / 癌遺伝子 / RAS

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, 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] 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
  • 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] 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) Issue: 6 Pages: 532-6
  • DOI: 10.1016/j.braindev.2013.07.009
  • Peer Reviewed / Open Access
• [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] 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) Issue: 7 Pages: 953-7
  • DOI: 10.1007/s00431-013-1977-8
  • Peer Reviewed
• [Journal Article] A transient myelodysplastic/myeloproliferative neoplasm in a patient with cardio-facio-cutaneous syndrome and a germline BRAF mutation (2013)
  • Author(s): Sekiguchi K, et al.
  • Journal Title: Am J Med Genet A Volume: 161 Issue: 10 Pages: 2600-2603
  • DOI: 10.1002/ajmg.a.36107
  • Peer Reviewed
• [Journal Article] MLL2 and KDM6A mutations in patients with Kabuki syndrome. (2013)
  • Author(s): Miyake N*, Koshimizu E, Okamoto N, Mizuno S, Ogata T,at all
  • Journal Title: Am J Med Genet A Volume: 161 Issue: 9 Pages: 2234-2243
  • DOI: 10.1002/ajmg.a.36072
  • Peer Reviewed
• [Journal Article] Ras/MAPK syndromes and childhood hemato-oncological diseases (2013)
  • Author(s): Aoki Y, Matsubara Y
  • Journal Title: Int J Hematol Volume: 97 Issue: 1 Pages: 30-36
  • DOI: 10.1007/s12185-012-1239-y
  • NAID: 10031144632
  • Peer Reviewed
• [Journal Article] A case of almost unilateral focal dermal hypoplasia resulting from a novel mutation in the PORCN gene (2013)
  • Author(s): Asano M, et al.
  • Journal Title: Acta Derm Venereol Volume: 93 Issue: 1 Pages: 120-121
  • DOI: 10.2340/00015555-1399
  • 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] 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] 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] Homozygous c. 14576G> A Variant of<I> RNF213</I> Predicts Early-Onset and Severe Form of Moyamoya Disease (2012)
  • Author(s): Miyatake S, Miyake N, Touho H, Nishimura-T, A, Kondo Y, Okada ; I, Tsurusaki ; Y, Doi H, Sakai H, Saitsu ; H, Shimojima K, Yamamoto T, Higurashi M, Kawahara, N, Kawauchi, H, Nagasaka, K, Okamoto N, Mori, T, Koyano S, Kuroiwa Y, Taguri M, Morita S, Matsuba S, Kure S, Matsumoto N
  • Journal Title: Neurology Volume: 78(11) Issue: 11 Pages: 803-10
  • DOI: 10.1212/wnl.0b013e318249f71f
  • 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) Issue: 4 Pages: 553-8
  • DOI: 10.1016/j.ymgme.2011.12.024
  • Peer Reviewed
• [Journal Article] Human variome project country nodes: Documenting genetic information within a country (2012)
  • Author(s): Patrinos GP, et al.
  • Journal Title: Hum Mutat. Volume: 33(11) Issue: 11 Pages: 1513-1519
  • DOI: 10.1002/humu.22147
  • Peer Reviewed
• [Journal Article] Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13 (2012)
  • Author(s): Kikuchi A, et al
  • Journal Title: Mol Genet Metab Volume: 105(A) Pages: 553-558
  • Peer Reviewed
• [Journal Article] Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe fonn of Moyamoya disease (2012)
  • Author(s): Miyatake S, et al
  • Journal Title: Neurology Volume: 78(11) Pages: 803-810
  • Peer Reviewed
• [Journal Article] Epilepsy in RAS/MAPK syndrome : Two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review (2012)
  • Author(s): Adachi M, et al
  • Journal Title: Seizure Volume: 21(1) Issue: 1 Pages: 55-60
  • DOI: 10.1016/j.seizure.2011.07.013
  • 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
• [Journal Article] Mutation (variation) databases and registries : a rationale for coordination of efforts (2011)
  • Author(s): Auerbach AD, et al
  • Journal Title: Nature Rev Genet Volume: 12(23) Pages: 881-881
  • Peer Reviewed
• [Journal Article] Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His (2011)
  • Author(s): Wakabayashi Y, et al
  • Journal Title: Am J Med Genet A Volume: 155A(10) Issue: 10 Pages: 2529-2533
  • DOI: 10.1002/ajmg.a.34194
  • Peer Reviewed
• [Journal Article] Implications of prenatal diagnosis of the fetus with both interstitial deletion and a small marker ring originating from chromosome 5 (2011)
  • Author(s): Ohashi H, et al
  • Journal Title: Am J Med Genet A Volume: 155A(1) Issue: 1 Pages: 192-196
  • DOI: 10.1002/ajmg.a.33764
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies RNF213 as the first Moyamoya disease gene (2011)
  • Author(s): Kamada F, et al
  • Journal Title: J Hum Genet Volume: 56(1) Issue: 1 Pages: 34-40
  • DOI: 10.1038/jhg.2010.132
  • 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. 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
• [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] Noonan症候群類縁疾患と小児血液腫瘍におけるCBLの分子遺伝学的解析 (2012)
  • Author(s): 齋藤由佳
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 久留米
• [Presentation] コステロ症候群・CFC症候群の全国実態調査とその病態の解明に関する研究 (2012)
  • Author(s): 阿部裕
  • 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, 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
• [Presentation] HRAS mutants identified in Costello syndrome patients can induce cellular senescence : possible implications for the pathogenesis of Costello syndrome (2011)
  • Author(s): 新堀哲也, 他
  • Organizer: International meeting on genetic syndromes of the Ras/MAPK pathway
  • Place of Presentation: アメリカ、シカゴ
• [Presentation] Epidemiological features of Costello Syndrome and Cardio-facio-cutaneous Syndrome : findings from the first nationwide survey (2011)
  • Author(s): 阿部裕, 他
  • Organizer: 12th International Congress of Huma Genetics
  • Place of Presentation: アメリカ、シカゴ
• [Presentation] 次世代シークエンサーによる遺伝性疾患研究・診療のパラダイムシフト
  • Author(s): 松原洋一
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
  • Invited
• [Remarks] RAS/MAPK症候群ホームページ
  • URL: http://www.medgen.med.tohoku.ac.jp/
• [Remarks]
  • URL: http://www.medgen.med.tohoku.ac.jp/