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

• 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
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2011: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: モヤモヤ病 / 発症機序 / 遺伝子検査 / 遺伝子診断

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 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] Infantile Tullio Phenomenon (2012)
  • Author(s): Kakisaka Y, Hino-Fukuyo N, Miyazaki H, Kure S
  • Journal Title: J Pediatr Volume: 162 Issue: 4 Pages: 880-880
  • 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, and Ishii N.
  • Journal Title: PLoS ONE Volume: 7(6) Issue: 6 Pages: e37892-e37892
  • 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(4) Issue: 4 Pages: 553-8
  • 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 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
• [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, Yamamoto T, Matsubara Y, Kure S, Matsumoto N.
  • Journal Title: Ｎｅｕｒｏｌｏｇｙ Volume: 78 Pages: 803-810
  • 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 Metabol Volume: 105 Pages: 553-558
  • 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] 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 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, RNF213 (2012)
  • Author(s): Kure S
  • Organizer: (Invited lecture) NAVBO Workshops in Vascular Biology 2012
  • Place of Presentation: Pacific Grove, CA, USA
• [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
• [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
• [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