Development of a genetic test to evaluate the risk for Moyamoya disease

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659512
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: KURE Shigeo 東北大学, 大学院・医学系研究科, 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): 2011 – 2012
• Keywords: モヤモヤ病 / 発症機序 / 遺伝子検査

Research Abstract

Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. A genome-wide association study was performed, which resulted in a strong association of chromosome17q25-ter with MMD risk. A single haplotype consisting of seven SNPs at the RNF213 locuswas tightly associated with MMD (P=5.3x10-10). Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P=1.2x10-43, odds ratio=190.8). We developed a genetic testing method for this founder mutation by using CASSOH (competitive allele-specific short oligonucleotide hybridization). The CASSOH 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] Homozygous c.14576G>A variant in RNF213 is the strong predictor for 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, M.D., Yamamoto 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, and Matsumoto N
  • Journal Title: Neurology Volume: 78 Pages: 803-810
  • DOI: DOI:10.1212/WNL.0b013e318249f71f
  • Peer Reviewed
• [Journal Article] Infantile Tullio Phenomenon (2012)
  • Author(s): Kakisaka Y, Hino-Fukuyo N, Miyazaki H, Kure S
  • Journal Title: J Pediatr Volume: 162 Pages: 880
  • DOI: DOI:10.1016/j.jpeds.2012.10.049
  • Peer Reviewed
• [Journal Article] Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice (2012)
  • Author(s): Moriya K, Suzuki M, Watanabe Y, Takahashi T, Aoki, Y, Uchiyama T, Kumaki, S, Sasahara Y, Minegishi M, Kure S, Tsuchiya S, Sugamura K, Ishii N
  • Journal Title: PLoS One Volume: 7 Pages: e37892
  • DOI: DOI:10.1371/journal.pone.0037892
  • 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 Pages: 553-558
  • DOI: DOI:10.1016/j.ymgme.2011.12.024
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding the glycine cleavage system predispose to neural tube defects (2012)
  • Author(s): Narisawa A, Komatsuzaki S, Kikuchi A, Niihori T, Aoki Y, Fujiwara K, Tanemura M, Hata A, Suzuki Y, Relton CL, Stanier P, Grinham J, Leung KY, Partridge D, Robinson A, Stone V, Gustavsson P, Copp AJ, Greene NDE, Tominaga T, Matsubara Y, Kure S
  • Journal Title: Hum Mol Genet Volume: 21 Pages: 1496-1503
  • DOI: 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, Haginoya K, Kikuchi A, Nakayama T, Kakisaka Y, Numata Y, Kobayashi T, Hino-Fukuyo N Fujiwara I, Kure S
  • Journal Title: J Neurol Sci Volume: 315 Pages: 77-81
  • DOI: DOI:10.1016/j.jns.2011.11.025
  • Peer Reviewed
• [Journal Article] A genome-wide association study identifies RNF213 as the first Moyamoya disease gene (2011)
  • Author(s): Kamada F., Aoki, Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori, T Ono, M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S
  • Journal Title: J Hum Genet Volume: 56 Pages: 34-40
  • DOI: DOI:10.1038/jhg.2010.132
  • Peer Reviewed
• [Journal Article] Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia (2011)
  • Author(s): Tsuyusaki Y, Shimbo H, Wada T, Iai M, Tsuji M, Yamashita S, Aida N, Kure S, Osaka H
  • Journal Title: Brain Dev Volume: 34 Pages: 72-75
  • DOI: DOI:10.1016/j.braindev.2011.01.005
  • Peer Reviewed
• [Presentation] モヤモヤ病遺伝子を追う (2013)
  • Author(s): 呉繁夫
  • Organizer: 広島先天代謝異常症治療研究会
  • Place of Presentation: 広島
  • Year and Date: 2013-02-08
• [Presentation] Identification of Moyamoya disease gene, RNF213 (2012)
  • Author(s): Kure S
  • Organizer: (Invited lecture) NAVBO Workshops in Vascular Biology 2012
  • Place of Presentation: Pacific Grove, CA, USA
  • Year and Date: 20121014-18
• [Presentation] モヤモヤ病感受性遺伝子の同定とその臨床的意義 (2012)
  • Author(s): 呉繁夫
  • Organizer: 日本小児神経学会総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120517-19
• [Presentation] Identification of Moyamoya disease gene and its clinical significance (2012)
  • Author(s): Kure S
  • Organizer: GCOE (Global center of excellence) meeting
  • Place of Presentation: Singapore
  • Year and Date: 2012-08-20
• [Presentation] モヤモヤ病遺伝子を追う特別講演 (2012)
  • Author(s): 呉繁夫
  • Organizer: 日本小児科学会秋田地方会
  • Place of Presentation: 秋田市
  • Year and Date: 2012-07-21
• [Presentation] モヤモヤ病感受性遺伝子の同定とその臨床的意義 (2012)
  • Author(s): 呉繁夫
  • Organizer: 日本小児神経学会関東地方会特別講演
  • Place of Presentation: 宇都宮
  • Year and Date: 2012-03-17
• [Presentation] Identification of Moyamoya disease gene (2011)
  • Author(s): Kure S
  • Organizer: Annual meeting of American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] モヤモヤ病感受性遺伝子の同定 (2011)
  • Author(s): 呉繁夫
  • Organizer: 日本小児神経学会
  • Place of Presentation: 横浜
  • Year and Date: 20110526-28