Identification of novel susceptibility genes associated with moyamoya disease without pathogenic variants in RNF213

• Project/Area Number: 16K10740
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Akagawa Hiroyuki 東京女子医科大学, 医学部, 准教授 (60398807)
• Co-Investigator(Kenkyū-buntansha): 糟谷 英俊 東京女子医科大学, 医学部, 教授 (50169455) ; 恩田 英明 東京女子医科大学, 医学部, 非常勤講師 (60185692) ; 米山 琢 東京女子医科大学, 医学部, 講師 (90318105)
• Research Collaborator: Nariai Tadashi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: もやもや病 / 感受性遺伝子 / 類もやもや病 / RNF213遺伝子 / CCER2遺伝子 / レアバリアント / 次世代シーケンサー / 脳神経疾患

Outline of Final Research Achievements

The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in Japanese patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Next-generation sequencing and following rare-variant association analysis identified CCER2 as a novel susceptibility gene to MMD. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.

Academic Significance and Societal Importance of the Research Achievements

もやもや病は世界的にみても本邦に最も患者が多い。有病率は人口10万人に対して3～10人の比較的稀な疾患ではあるが、近年の研究では一見して生活習慣病による脳血管狭窄であっても遺伝学的な要因が共通なものも存在することが明らかになってきた。このような遺伝学的要因は複数存在するが、これらを特定できれば新たな診断法や治療法の開発に応用することができ、近年社会的な注目度が高まっている脳卒中の医療において大きな貢献となることが期待される。本課題ではその一端を特定するに至った。

Research Products

• [Journal Article] Rare and Low-Frequency Variants in RNF213 Confer Susceptibility to Moyamoya Syndrome Associated with Hyperthyroidism (2019)
  • Author(s): Nomura Shunsuke、Akagawa Hiroyuki、Yamaguchi Koji、Ishikawa Tatsuya、Kawashima Akitsugu、Kasuya Hidetoshi、Mukawa Maki、Nariai Tadashi、Maehara Taketoshi、Okada Yoshikazu、Kawamata Takakazu
  • Journal Title: World Neurosurgery Volume: In press Pages: e460-e466
  • DOI: 10.1016/j.wneu.2019.03.172
  • Peer Reviewed
• [Journal Article] Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease (2019)
  • Author(s): Nomura Shunsuke、Yamaguchi Koji、Akagawa Hiroyuki、Kawashima Akitsugu、Moteki Yosuke、Ishikawa Tatsuya、Aihara Yasuo、Saito Taiichi、Okada Yoshikazu、Kawamata Takakazu
  • Journal Title: Cerebrovascular Diseases Volume: In press Issue: 3-4 Pages: 1-7
  • DOI: 10.1159/000499699
  • Peer Reviewed
• [Journal Article] Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease (2018)
  • Author(s): Akagawa Hiroyuki、Mukawa Maki、Nariai Tadashi、Nomura Shunsuke、Aihara Yasuo、Onda Hideaki、Yoneyama Taku、Kudo Takumi、Sumita Kazutaka、Maehara Taketoshi、Kawamata Takakazu、Kasuya Hidetoshi
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 17060-17060
  • DOI: 10.1038/hgv.2017.60
  • Peer Reviewed / Open Access
• [Journal Article] Letter to the Editor. Influence of rare RNF213 variants other than p.R4810K on the clinical outcomes of moyamoya disease (2018)
  • Author(s): Nomura Shunsuke、Kawashima Akitsugu、Akagawa Hiroyuki、Kawamata Takakazu
  • Journal Title: Journal of Neurosurgery Volume: 129 Issue: 2 Pages: 563-565
  • DOI: 10.3171/2018.1.jns173211
  • Peer Reviewed
• [Journal Article] Letter to the Editor. Influence of rare RNF213 variants other than p.R4810K on the clinical outcomes of moyamoya disease (2018)
  • Author(s): Shunsuke Nomura, Akitsugu Kawashima, Hiroyuki Akagawa, Takakazu Kawamata
  • Journal Title: Journal of Neurosurgery Volume: in press
  • Peer Reviewed
• [Journal Article] Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease. (2017)
  • Author(s): Mukawa M, Nariai T, Onda H, Yoneyama T, Aihara Y, Hirota K, Kudo T, Sumita K, Maehara T, Kawamata T, Kasuya H, Akagawa H.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 26 Issue: 1 Pages: 150-161
  • DOI: 10.1016/j.jstrokecerebrovasdis.2016.09.003
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] もやもや病・もやもや症候群の遺伝子解析 (2019)
  • Author(s): 赤川浩之, 野村俊介, Boris Krischek, 武川麻紀, 前原健寿, 成相直, 糟谷英俊, 川俣貴一
  • Organizer: Stroke2019第44回日本脳卒中学会学術総会
  • Invited
• [Presentation] Exome sequencing identified CCER2 as a novel candidate gene for Moyamoya disease (2018)
  • Author(s): Hiroyuki Akagawa
  • Organizer: 5th International Moyamoya Meeting (IMM 2018)
  • Int'l Joint Research / Invited
• [Presentation] もやもや病の病態と治療：感受性遺伝子解析の観点から (2018)
  • Author(s): 赤川 浩之、野村 俊介、Boris Krischek、武川 麻紀 、前原 健寿、成相 直、糟谷 英俊、川俣 貴一
  • Organizer: 第77回日本脳神経外科学会学術総会
  • Invited
• [Presentation] Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease. (2018)
  • Author(s): Hiroyuki Akagawa
  • Organizer: 5th International Moyamoya meeting (Seoul, Korea)
  • Int'l Joint Research / Invited
• [Presentation] 次世代シーケンサーによる類もやもや病の遺伝子解析 (2018)
  • Author(s): 野村俊介, 赤川浩之, 川島明次, 山口浩司, 石川達也, 武川麻紀, 成相直, 糟谷英俊, 川俣貴一
  • Organizer: 第47回日本脳卒中の外科学会学術総会
• [Presentation] Genetics of Moyamoya disease (2017)
  • Author(s): Hiroyuki Akagawa
  • Organizer: 5th International Neurosurgical Conference on MoyaMoya Disease（煙台市、中国）
  • Int'l Joint Research / Invited
• [Presentation] 次世代シーケンサーによるもやもや病の感受性遺伝子解析 (2017)
  • Author(s): 野村俊介, 赤川浩之, 山口浩司, 石川達也, 川島明次, 武川麻紀, 成相直, 糟谷英俊, 川俣貴一
  • Organizer: 日本脳神経外科学会第76回学術総会
• [Book] 医学と薬学【日常診療でよく目にする脳外科疾患(II)】脳神経外科領域の遺伝子診断 (2018)
  • Author(s): 赤川浩之
  • Total Pages: 8
  • Publisher: (株)自然科学社