Cerebral vascular abnormality in carriers of the RNF213 risk variant detected by a new genetic test

• Project/Area Number: 24659486
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: KURE Shigeo 東北大学, 医学(系)研究科(研究院), 教授 (10205221)
• Co-Investigator(Kenkyū-buntansha): TOMINAGA Teiji 東北大学, 大学院医学系研究科, 教授 (00217548)
• Project Period (FY): 2012-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 小児神経学 / 保因者診断 / モヤモヤ病 / 疾患感受性遺伝子 / RNF213遺伝子多型 / 遺伝子検査

Research Abstract

Moyamoya disease (MMD) manifests progressive bilateral internal carotid artery stenosis and abnormal collateral vessels. A genome-wide association study was performed, which showed a strong association of chromosome 17q25-ter with MMD risk. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD risk. Mutational analysis of RNF213 revealed a founder mutation, c.14576G>A, in 73% of non-familial MMD cases and 1.4% of controls; carriers of this mutation have increased risk of MMD (P=1.2x10-43, odds ratio=190.8). We developed a genetic testing method for this founder mutation. The new method enables us to detect the target mutation with immunechromatography without expertize, which would be useful for evaluation of a risk for MMD risk in bedside and clinic.

Research Products

• [Journal Article] Development of a de novo arteriovenous malformation after bilateral revascularization surgery in a child with moyamoya disease (2014)
  • Author(s): Fujimura M, Kimura N, Ezura M, Niizuma K, Uenohara H, Tominaga T.
  • Journal Title: J Neurosurg Pediatr Volume: (印刷中)
  • 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] JAM Trial Investigators. Effects of extracranial-intracranial bypass for patients with hemorrhagic moyamoya disease : results of the Japan adult moyamoya trial (2014)
  • Author(s): Miyamoto S, Yoshimoto T, Hashimoto N, Okada Y, Tsuji I, Tominaga T, Nakagawara J, Takahashi JC.
  • Journal Title: Stroke Volume: 45(5) Pages: 1415-21
  • Peer Reviewed
• [Journal Article] Efficacy of Superficial Temporal Artery-Middle Cerebral Artery Double Anastomoses in a Patient with Rapidly Progressive Moyamoya Disease : Case Report (2014)
  • Author(s): Yokosawa M, Hayashi T, Shirane R, Tominaga T.
  • Journal Title: Neurol Med Chir (Tokyo) Volume: (Epub ahead of print)
  • NAID: 130004699228
  • Peer Reviewed
• [Journal Article] Minocycline prevents focal neurological deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease (2014)
  • Author(s): Fujimura M, Niizuma K, Inoue T, Sato K, Endo H, Shimizu H, T ominaga T
  • Journal Title: Neurosurgery Volume: 74(2) Issue: 2 Pages: 163-70
  • DOI: 10.1227/neu.0000000000000238
  • Peer Reviewed
• [Journal Article] Abdominal and lower back pain in pediatric idiopathic stabbing headache. (2014)
  • Author(s): Kakisaka Y, Ohara T, Hino-Fukuyo N, Uematsu M, Kure S
  • Journal Title: Pediatrics Volume: 133 Issue: 1 Pages: e245-e247
  • DOI: 10.1542/peds.2013-0793
  • Peer Reviewed
• [Journal Article] IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome. (2014)
  • Author(s): Moriya K, Kaneko MK, Liu X, Hosaka M, Fujishima F, Sakuma J, Ogasawara S, Watanabe M, Sasahara Y, Kure S, Kato Y
  • Journal Title: Cancer Sci. Volume: 105 Issue: 3 Pages: 359-62
  • DOI: 10.1111/cas.12337
  • Peer Reviewed
• [Journal Article] Moyamoya disease in pregnancy : a single institute experience (2013)
  • Author(s): Fujimura M, Akagi K, Uenohara H, Tominaga T.
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 53(8) Pages: 561-4
  • NAID: 10031178566
  • Peer Reviewed
• [Journal Article] Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector (2013)
  • Author(s): Horino S, Uchiyama T, So T, Nagashima H, Sun SL, Sato M, Asao A, Haji Y, Sasahara Y, Candotti F, Tsuchiya S, Kure S, Sugamura K, and Ishii N
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e71594-e71594
  • DOI: 10.1371/journal.pone.0071594
  • Peer Reviewed
• [Journal Article] T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation. (2013)
  • Author(s): Watanabe Y, Sasahara Y, Ramesh N, Massaad MJ, Yeng Looi C, Kumaki S, Kure S, Geha RS, Tsuchiya S.
  • Journal Title: J Allergy Clin Immunol. Volume: 132 Issue: 3 Pages: 648-655
  • DOI: 10.1016/j.jaci.2013.03.046
  • Peer Reviewed
• [Journal Article] Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease. (2013)
  • Author(s): Numata Y, Morimura T, Nakamura S, Hirano E, Kure S, Goto YI, Inoue, K.
  • Journal Title: The Journal of Biological Chemistry Volume: 288 Issue: 11 Pages: 7451-7466
  • DOI: 10.1074/jbc.m112.435388
  • 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] Temporal profile of de novo development of moyamoya vasculopathy in an adult : case report (2012)
  • Author(s): Shimoda Y, Fujimura M, Inoue T, Shimizu H, Tominaga T.
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 52(5) Pages: 339-42
  • NAID: 10030314630
  • Peer Reviewed
• [Journal Article] Lessons learned from moyamoya disease : outcome of direct/indirect revascularization surgery for 150 affected hemispheres (2012)
  • Author(s): Fujimura M, Tominaga T.
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 52(5) Pages: 327-32
  • NAID: 10030314562
  • Peer Reviewed
• [Journal Article] Efficacy of prophylactic blood pressure lowering according to a standardized postoperative management protocol to prevent symptomatic cerebral hyperperfusion after direct revascularization surgery for moyamoya disease (2012)
  • Author(s): Fujimura M, Inoue T, Shimizu H, Saito A, Mugikura S, Tominaga T
  • Journal Title: Cerebrovasc Dis Volume: 33(5) Issue: 5 Pages: 436-45
  • DOI: 10.1159/000336765
  • 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] Hypoperfusion in caudate nuclei in patients with brain-lung-thyroid syndrome (2012)
  • Author(s): Uematsu M
  • Journal Title: J Neurol Sci Volume: 315 Issue: 1-2 Pages: 77-81
  • DOI: 10.1016/j.jns.2011.11.025
  • Peer Reviewed
• [Journal Article] Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia (2012)
  • Author(s): Tsuyusaki Y
  • Journal Title: Brain Dev Volume: 341 Issue: 1 Pages: 72-75
  • DOI: 10.1016/j.braindev.2011.01.005
  • Peer Reviewed
• [Presentation] Identification of a susceptibility gene for Moyamoya disease (2013)
  • Author(s): Kure S.
  • Organizer: in 3rd Inetrnational Moyamoya disease Meeting
  • Place of Presentation: Sapporo, Japan
  • Invited
• [Presentation] Diagnosis of Moyamoya Disease; Revisit of Suzuki's Angiographic Grading (2013)
  • Author(s): Tominaga T.
  • Organizer: in 3rd Inetrnational Moyamoya disease Meeting
  • Place of Presentation: Sapporo, Japan
  • Invited
• [Presentation] Identification of a susceptibility gene for Moyamoya disease (2012)
  • Author(s): Kure S.
  • Organizer: Genetics and Genomics of Vascular Disease Workshop II in NAVBO Workshops in Vascular Biology 2012
  • Place of Presentation: in Pacific Grove, CA, Monterey,USA
  • Invited
• [Presentation] Identification of a susceptibility gene for Moyamoya disease in Japanese patients with Moyamoya disease and its clinical significance (2012)
  • Author(s): Kure S, Kamada F, Aoki Y, Abe Y, Kikuchi A, Komatsuzaki S, Kanno J, Matsubara Y, Touho H, Miyatake S, Matsumoto N.
  • Organizer: 54th Annual meeting of Society of Child Neurology
  • Place of Presentation: Sapporo, Japan
• [Presentation] モヤモヤ病の疾患感受性遺伝子の同定 (2011)
  • Author(s): 呉繁夫
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 横浜
• [Presentation] モヤモヤ病遺伝的要因の解明-疾患感受性遺伝子と創始者変異の同定 (2011)
  • Author(s): 呉繁夫、鎌田文顕、青木洋子、阿部裕、新堀哲也、小松崎匠子、菊池敦生、菅野潤子、土屋滋、松原洋一
  • Organizer: 第114回日本小児科学会学術集会
  • Place of Presentation: 東京