Search for new theraputic targets for intracranial artery stenosis

• Project/Area Number: 19K09473
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: The University of Tokyo
• Principal Investigator: Miyawaki Satoru 東京大学, 医学部附属病院, 講師 (70407914)
• Co-Investigator(Kenkyū-buntansha): 中冨 浩文 東京大学, 医学部附属病院, 准教授 (10420209) ; 齊藤 延人 東京大学, 医学部附属病院, 教授 (60262002)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脳血管狭窄 / RNF213 / GWAS / PheWAS / whole exome sequence / 遺伝子解析

Outline of Research at the Start

我々はこれまRNF213という遺伝子の変異（c.14576G>A, p. R4859K, rs112735431）が、脳梗塞の主たる原因である脳血管狭窄の発症に非常に強い関連をもつことを明らかにし、RNF213に関する様々な疫学的・機能的解析に関して研究成果を発表してきた。本研究において、RNF213変異に加えて脳血管狭窄、しいては脳梗塞の発症に関わる修飾因子となる遺伝子・分子の同定を目指す。

Outline of Final Research Achievements

In this study, we aimed to elucidate the pathogenesis of intracranial artery stenosis through various genetic analyses. First, we identified ICAS-associated rare RNF213 variants by targeting the entire RNF213. Second, we searched the whole genome region for variants associated with intracranial artery stenosis and found that the only significant associated variant was RNF213 p.Arg4810Lys. Finally, we searched for genetic factors other than RNF213 p.Arg4810Lys that determine the severity of intracranial artery stenosis and identified a candidate gene. Further functional analysis of this gene will help elucidate the mechanism of intracranial artery stenosis.

Academic Significance and Societal Importance of the Research Achievements

脳血管狭窄に関して、発展的な遺伝子解析研究を行い新たな知見を多く得た。脳血管狭窄に限定した遺伝子解析研究は独自性が高く学術的意義は高いと考えられる。脳血管狭窄の重症度に関連する同定しており、さらなる研究の発展が期待される。脳血管狭窄のは日本はじめとした東アジアに多く発症することが知られており、その病態解明は社会的意義が高いと考える。

Research Products

• [Journal Article] Symptomatic and Stenotic Developmental Venous Anomaly with Pontine Capillary Telangiectasia: A Case Report with Genetic Considerations (2022)
  • Author(s): ISHIGAMI Daiichiro、KOIZUMI Satoshi、MIYAWAKI Satoru、HONGO Hiroki、TERANISHI Yu、MITSUI Jun、SAITO Nobuhito
  • Journal Title: NMC Case Report Journal Volume: 9 Issue: 0 Pages: 139-144
  • DOI: 10.2176/jns-nmc.2022-0022
  • ISSN: 2188-4226
  • Year and Date: 2022-12-31
  • Peer Reviewed / Open Access
• [Journal Article] Advances in Molecular Biological and Translational Studies in World Health Organization Grades 2 and 3 Meningiomas: A Literature Review (2022)
  • Author(s): Okano A, Miyawaki S, Teranishi Y, Ohara K, Hongo H, Sakai Y, Ishigami D, Nakatomi H, Saito N
  • Journal Title: Neurologia medico-chirurgica Volume: 62 Issue: 8 Pages: 347-360
  • DOI: 10.2176/jns-nmc.2022-0114
  • ISSN: 0470-8105, 1349-8029
  • Year and Date: 2022-08-15
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of NF2 alteration in grade I meningiomas revisited; prognostic impact integrated with extent of resection, tumour location, and Ki-67 index (2022)
  • Author(s): Teranishi Y, Okano A, Miyawaki S, Ohara K, Ishigami D, Hongo H, Dofuku S, Takami H, Mitsui J, Ikemura M, Komura D, Katoh H, Ushiku T, Ishikawa S, Shin M, Nakatomi H, Saito N.
  • Journal Title: Acta Neuropathol Commun Volume: 10(1):76 Issue: 1
  • DOI: 10.1186/s40478-022-01377-w
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study (2022)
  • Author(s): Dofuku S, Sonehara K, Miyawaki S, Sakaue S, Imai H, Shimizu M, Hongo H, Shinya Y, Ohara K, Teranishi Y, Okano A, Ono H, Nakatomi H, Teraoka A, Yamamoto K, Maeda Y, Nii T, Kishikawa T, Suzuki K, Hirata J, Takahashi M, Matsuda K, Kumanogoh A, Matsuda F, Okada Y, Saito N.
  • Journal Title: Transl Stroke Res. Volume: - Issue: 3 Pages: 322-333
  • DOI: 10.1007/s12975-022-01049-w
  • Peer Reviewed
• [Journal Article] Early prediction of functional prognosis in neurofibromatosis type 2 patients based on genotype-phenotype correlation with targeted deep sequencing (2022)
  • Author(s): Yu Teranishi、Satoru Miyawaki、Hirofumi Nakatomi、Kenta Ohara、Hiroki Hongo、Shogo Dofuku、Atsushi Okano、Shunsaku Takayanagi、Takahiro Ota、Jun Yoshimura、Wei Qu、Jun Mitsui、Shinichi Morishita、Shoji Tsuji、Nobuhito Saito
  • Journal Title: Scientific Reports Volume: 12(1) Issue: 1 Pages: 9543-9543
  • DOI: 10.1038/s41598-022-13580-9
  • Peer Reviewed / Open Access
• [Journal Article] NF2 Alteration/22q Loss Is Associated with Recurrence in WHO Grade 1 Sphenoid Wing Meningiomas (2022)
  • Author(s): Sakai Y, Miyawaki S, Teranishi Y, Okano A, Ohara K, Hongo H, Ishigami D, Shimada D, Mitsui J, Nakatomi H, Saito N.
  • Journal Title: Cancers (Basel) Volume: 14(13):3183 Issue: 13 Pages: 3183-3183
  • DOI: 10.3390/cancers14133183
  • Peer Reviewed / Open Access
• [Journal Article] Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations (2022)
  • Author(s): Hongo Hiroki、Miyawaki Satoru、Teranishi Yu、Mitsui Jun、Katoh Hiroto、Komura Daisuke、Tsubota Kinya、Matsukawa Takashi、Watanabe Masakatsu、Kurita Masakazu、Yoshimura Jun、Dofuku Shogo、Ohara Kenta、Ishigami Daiichiro、Okano Atsushi、Kato Motoi、Hakuno Fumihiko、Takahashi Ayaka、Kunita Akiko、Ishiura Hiroyuki、et al.
  • Journal Title: Angiogenesis Volume: 26 Issue: 1 Pages: 37-52
  • DOI: 10.1007/s10456-022-09846-5
  • Peer Reviewed / Open Access
• [Journal Article] Genetics of brain arteriovenous malformations and cerebral cavernous malformations (2022)
  • Author(s): Hongo Hiroki、Miyawaki Satoru、Teranishi Yu、Ishigami Daiichiro、Ohara Kenta、Sakai Yu、Shimada Daisuke、Umekawa Motoyuki、Koizumi Satoshi、Ono Hideaki、Nakatomi Hirofumi、Saito Nobuhito
  • Journal Title: Journal of Human Genetics Volume: 68 Issue: 3 Pages: 157-167
  • DOI: 10.1038/s10038-022-01063-8
  • Peer Reviewed / Open Access
• [Journal Article] RNF213 p.Arg4810Lys Heterozygosity in Moyamoya Disease Indicates Early Onset and Bilateral Cerebrovascular Events. (2021)
  • Author(s): Ishigami D, Miyawaki S, Imai H, Shimizu M, Hongo H, Dofuku S, Ohara K, Teranishi Y, Shimada D, Koizumi S, Ono H, Hirano Y, Segawa M, Nakatomi H, Saito N.
  • Journal Title: Transl Stroke Res. Volume: 13(3) Issue: 3 Pages: 410-419
  • DOI: 10.1007/s12975-021-00956-8
  • Peer Reviewed
• [Journal Article] A Case of Brainstem Intraparenchymal Schwannoma with Genetic Analysis. (2021)
  • Author(s): Ishigami D, Miyawaki S, Nakatomi H, Takayanagi S, Teranishi Y, Ohara K, Hongo H, Dofuku D, Kin T, Abe H, Mitsui J, Komura D, Katoh H, Ishikawa S, Saito N.
  • Journal Title: BMC Med Genomics. Volume: 18 Issue: 1 Pages: 205-205
  • DOI: 10.1186/s12920-021-01049-z
  • Peer Reviewed / Open Access
• [Journal Article] Spontaneous regression of a symptomatic developmental venous anomaly with capillary stain. (2021)
  • Author(s): Hirata T, Miyawaki S, Koizumi S, Teranishi Y, Ishikawa O, Saito N.
  • Journal Title: Interv Neuroradiol. Volume: - Issue: 3 Pages: 0-0
  • DOI: 10.1177/15910199211032470
  • Peer Reviewed
• [Journal Article] Differences in clinical features among different onset patterns in moyamoya disease. (2021)
  • Author(s): Hirano Y, Miyawaki S, Imai H, Hongo H, Teranishi Y, Dofuku S, Ishigami D, Ohara K, Koizumi S, Ono H, Nakatomi H and Saito N.
  • Journal Title: J Clin Med. Volume: 10(13) Pages: 2815-2815
  • Peer Reviewed / Open Access
• [Journal Article] Changes in the risk of stroke in dialysis patients: A retrospective analysis over the last 40 years. (2021)
  • Author(s): Aono T, Shinya Y, Miyawaki S, Kumagai I, Sugiyama T, Takenobu A, Shin M, Saito N and Teraoka A.
  • Journal Title: Toxins (Basel). Volume: 13(5) Issue: 5 Pages: 350-350
  • DOI: 10.3390/toxins13050350
  • Peer Reviewed / Open Access
• [Journal Article] Associations of pathological diagnosis and genetic abnormalities in meningiomas with the embryological origins of the meninges. (2021)
  • Author(s): Okano A, Miyawaki S, Hongo H, Dofuku S, Teranishi Y, Mitsui J, Tanaka M, Shin M, Nakatomi H, Saito N.
  • Journal Title: Sci Rep. Volume: 11(1) Issue: 1 Pages: 6987-6987
  • DOI: 10.1038/s41598-021-86298-9
  • Peer Reviewed / Open Access
• [Journal Article] 【疾患ゲノム研究の最前線】脳血管疾患のゲノム研究最前線. (2021)
  • Author(s): 宮脇 哲
  • Journal Title: BIO Clinica Volume: 36 Pages: 408-412
  • Peer Reviewed
• [Journal Article] Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2. (2020)
  • Author(s): Teranishi Y.、Miyawaki S.、Hongo H.、Dofuku S.、Okano A.、Takayanagi S.、Ota T.、Yoshimura J.、Qu W.、Mitsui J.、Nakatomi H.、Morishita S.、Tsuji S.、Saito N.
  • Journal Title: J Med Genet Volume: なし Issue: 10 Pages: 701-711
  • DOI: 10.1136/jmedgenet-2020-106973
  • Peer Reviewed
• [Journal Article] Risk Factors and Outcomes of Cerebral Stroke in End-Stage Renal Disease Patients Receiving Hemodialysis (2020)
  • Author(s): Shinya Y, Miyawaki S, Kumagai I, Takenobu A, Saito N, Teraoka A
  • Journal Title: Journal of stroke and cerebrovascular diseases Volume: 29(4) Issue: 4 Pages: 104657-104657
  • DOI: 10.1016/j.jstrokecerebrovasdis.2020.104657
  • Peer Reviewed
• [Journal Article] De Novo Development of Moyamoya Disease after Stereotactic Radiosurgery for Brain Arteriovenous Malformation in a Patient With RNF213 p.Arg4810Lys (rs112735431) (2020)
  • Author(s): Torazawa S, Miyawaki S, Shinya Y, Kawashima M, Hasegawa H, Dofuku S, Uchikawa H, Kin T, Shin M, Nakatomi H, Saito N.
  • Journal Title: World Neurosurgery Volume: 140(8) Pages: 276-282
  • DOI: 10.1016/j.wneu.2020.05.068
  • Peer Reviewed
• [Journal Article] Hemorrhagic onset intracranial artery dissection of middle cerebral artery followed by progressive arterial stenosis with genetic variant RNF213 p.Arg4810Lys (rs112735431) (2020)
  • Author(s): Shinya Y, Miyawaki S, Nakatomi H, Shin M, Teraoka A, Saito N
  • Journal Title: World Neurosurgery Volume: 141(9) Pages: 192-195
  • DOI: 10.1016/j.wneu.2020.04.241
  • Peer Reviewed
• [Journal Article] Comprehensive Investigation of RNF213 Nonsynonymous Variants Associated with Intracranial Artery Stenosis (2020)
  • Author(s): Hongo H, Miyawaki S, Imai H, Shimizu M, Yagi S, Mitsui J, Ishiura H, Yoshimura J, Doi K, Qu W, Teranishi Y, Okano A, Ono H, Nakatomi H, Shimizu T, Morishita S, Tsuji S, and Saito N
  • Journal Title: Scientific reports Volume: 10(1) Issue: 1 Pages: 11942-11942
  • DOI: 10.1038/s41598-020-68888-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between the onset pattern of adult moyamoya disease and risk factors for stroke (2020)
  • Author(s): Hirano Y, Miyawaki S, Imai H, Hongo H, Ohara K, Dofuku S, Teranishi Y, Nakatomi H, Saito N
  • Journal Title: Stroke Volume: 51(10) Issue: 10 Pages: 3124-3128
  • DOI: 10.1161/strokeaha.120.030653
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic Factor for Intracranial Artery Stenosis (2020)
  • Author(s): 宮脇 哲, 齊藤 延人
  • Journal Title: Japanese Journal of Neurosurgery Volume: 29 Issue: 10 Pages: 680-689
  • DOI: 10.7887/jcns.29.680
  • NAID: 130007930275
  • ISSN: 0917-950X, 2187-3100
  • Peer Reviewed
• [Journal Article] Vascular anomaly of the posterior circulation associated with intracranial lipoma-like lesion in the cerebral peduncle manifesting as oculomotor nerve palsy (2020)
  • Author(s): Hirano Yudai、Miyawaki Satoru、Yamada Keisuke、Shinya Yuki、Kin Taichi、Amemiya Shiori、Asakawa Yasumasa、Nakatomi Hirofumi、Saito Nobuhito
  • Journal Title: Journal of Clinical Neuroscience Volume: 72 Pages: 463-466
  • DOI: 10.1016/j.jocn.2019.12.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Short review of randomized controlled trials for Surgical Neurology International: Part II - drain-associated cerebrospinal fluid infections (2019)
  • Author(s): Lo Benjamin W. Y.、Fukuda Hitoshi、Miyawaki Satoru、Tsang Anderson C. O.、Koyanagi Masaomi
  • Journal Title: Surgical Neurology International Volume: 10 Pages: 39-39
  • DOI: 10.25259/sni-74-2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Surgical Management and Genetic aspects of Moyamoya disease (2022)
  • Author(s): Satoru Miyawaki
  • Organizer: WFNS Foundation ACNS Minimally Invasive Neurosurgery Web Seminar
  • Int'l Joint Research / Invited
• [Presentation] もやもや病脳血行再建術の周術期における対側半球の脳卒中イベントのリスクと対策 (2022)
  • Author(s): 宮脇哲、今井英明、本郷博貴、小泉聡、齊藤延人
  • Organizer: 第47回日本脳卒中学会学術集会
• [Presentation] もやもや病の遺伝子解析研究の最新の知見と未解決の課題 (2022)
  • Author(s): 宮脇哲、齊藤延人
  • Organizer: 第42回日本脳神経外科コングレス総会
  • Invited
• [Presentation] RNF213 genetic variant related diseases (2022)
  • Author(s): Satoru Miyawaki, Nobuhito Saito
  • Organizer: 16th World Federation of Interventional and Therapeutic Neuroradiology（WFITN2022）
  • Int'l Joint Research / Invited
• [Presentation] もやもや病の遺伝子解析研究の最新の知見 ―遺伝子型と表現型の関連― (2022)
  • Author(s): 宮脇哲、齊藤延人
  • Organizer: 日本脳神経外科学会 第81回学術総会
  • Invited
• [Presentation] もやもや病の脳血行再建術の周術期における対側半球の脳卒中イベント (2022)
  • Author(s): 宮脇哲、今井英明、本郷博貴、小泉聡、齊藤延人
  • Organizer: 日本脳神経外科学会第81回学術総会
• [Presentation] Cerebrovascular events in the contralateral hemisphere during the perioperative period of cerebral revascularization surgery for moyamoya disease (2022)
  • Author(s): Satoru Miyawaki, Hideaki Imai, Hiroki Hongo, Satoshi Koizumi, Nobuhito Saito
  • Organizer: World Internet Conference on Moyamoya Disease 2022
  • Int'l Joint Research
• [Presentation] Genome-Wide Association Study of Intracranial Artery Stenosis and Phenome-Wide Association Study of RNF213 p.Arg4810Lys (2022)
  • Author(s): Satoru Miyawaki, Shogo Dofuku, Kyuto Sonehara, Saori Sakaue, Hideaki Imai, Masahiro Shimizu, Hiroki Hongo, Yuki Shinya, Kenta Ohara, Yu Teranishi, Atsushi Okano, Hideaki Ono, Hirofumi Nakatomi, Akira Teraoka, Koichi Matsuda, Yukinori Okada, Nobuhito Saito
  • Organizer: World Internet Conference on Moyamoya Disease 2022
  • Int'l Joint Research
• [Presentation] もやもや病に対する脳血行再建術の周術期における対側半球の脳卒中イベントに対する対策 (2022)
  • Author(s): 宮脇哲、今井英明、本郷博貴、小泉聡、齊藤延人
  • Organizer: 第65回日本脳循環代謝学会学術集会
• [Presentation] もやもや病における脳卒中危険因子の重要性 (2021)
  • Author(s): 宮脇哲、平野雄大、今井英明、本郷博貴、小原健太、堂福翔吾、寺西裕、石神大一郎、中冨浩文、齊藤延人
  • Organizer: 第46回日本脳卒中学会学術集会
• [Presentation] もやもや病の遺伝子研究の最前線（シンポジウム） (2021)
  • Author(s): 宮脇哲、齊藤延人
  • Organizer: 第39回The Mt. Fuji Workshop on CVD 仙台
  • Invited
• [Presentation] Genetics of moyamoya disease. (2021)
  • Author(s): Satoru Miyawaki, Nobuhito Saito.
  • Organizer: 15th Japan-Korea Joint Conference on Surgery for Cerebral Stroke Seoul (Online conference)
  • Int'l Joint Research
• [Presentation] Familial Genetics of Moyamoya disease. (2021)
  • Author(s): Satoru Miyawaki, Nobuhito Saito.
  • Organizer: Cerebrovascular Symposium: Moyamoya Disease at New York University. Virtual Webinar.
  • Int'l Joint Research / Invited
• [Presentation] Rもやもや病:基礎病態の最新知見と臨床応用 (2020)
  • Author(s): 宮脇哲、齊藤延人
  • Organizer: 第40回日本脳神経外科コングレス
  • Invited
• [Presentation] 頭蓋内動脈狭窄症の遺伝的リスク因子RNF213バリアント (2020)
  • Author(s): 宮脇哲、今井英明、清水暢裕、堂福翔吾、本郷博貴、新谷祐貴、 小原健太、寺西裕、小野秀明、中冨浩文、清水庸夫、寺岡暉、斉藤延人
  • Organizer: 第45日本脳卒中学会学術集会
• [Presentation] 歯突起硬膜内に発生し嚢胞性病変を伴った偽腫瘍（ガングリオンシスト）の治療戦略 (2020)
  • Author(s): 宮脇哲、宮沢良太、山田恵祐、池村雅子、日向宗利、内川裕貴、金太一、高井敬介、中冨浩文、斉藤延人
  • Organizer: 第25回日本脳腫瘍の外科学会
• [Presentation] RNF213解析研究の現況と臨床応用の可能性 (2020)
  • Author(s): 宮脇哲 斉藤延人
  • Organizer: 第79回日本脳神経外科学会総会
  • Invited
• [Presentation] 成人もやもや病の発症形式による脳卒中リスク因子の違いの検証 (2020)
  • Author(s): 宮脇哲、平野雄大、今井英明、本郷博貴、小原健太、堂福翔吾、寺西裕、石神大一郎、中冨浩文、齊藤延人
  • Organizer: 第63回日本脳循環代謝学会
• [Presentation] RNF213変異を有する前方循環脳主幹動脈狭窄における椎骨脳底動脈の形態学的特徴の検討 (2019)
  • Author(s): 宮脇哲、清藤哲史、今井英明、清水暢裕、本郷博貴、堂福翔吾、岡野淳、寺西裕、小野秀明、中冨浩文、清水庸夫、斉藤延人
  • Organizer: 48回日本脳卒中の外科学会学術集会
• [Presentation] 頭蓋内血管狭窄の遺伝的要因 (2019)
  • Author(s): 宮脇哲、斉藤延人
  • Organizer: 第37回日本脳神経外科コングレス総会
  • Invited
• [Presentation] AVMに関連する遺伝子 (2019)
  • Author(s): 宮脇哲
  • Organizer: 第5回脳血管内治療軽井沢セミナー
  • Invited
• [Presentation] 脳血管障害と遺伝子 (2019)
  • Author(s): 宮脇哲
  • Organizer: 第28回昭和大学学士シンポジウム
  • Invited
• [Presentation] Genetic analysis of Moyamoya disease and intracranial stenosis. (2019)
  • Author(s): Satoru Miyawaki, Nobuhito Saito.
  • Organizer: 18th ASEAN Neurosurgical Society Meeting
  • Int'l Joint Research
• [Book] 最新主要文献でみる 脳神経外科学レビュー 2023-’24 (2022)
  • Author(s): 新井 一、齊藤延人、若林俊彦（監修） 宮脇哲
  • Total Pages: 440
  • Publisher: 総合医学社
  • ISBN: 4883787494
• [Book] 脳神経外科 Vol.50 No.1 (2022)
  • Author(s): 齊藤 延人（編） 宮脇哲
  • Total Pages: 256
  • Publisher: 医学書院
  • ISBN: 4260044869
• [Book] Annual Review 神経2020（2 脳血管障害 4 もやもや病感受性遺伝子RNF213の遺伝子解析研究の現況） (2020)
  • Author(s): 宮脇哲（監修 鈴木則宏 、荒木信夫、 宇川義一 、桑原聡 、 塩川芳昭）
  • Total Pages: 368
  • Publisher: 中外医学社
  • ISBN: 4498328485
• [Book] 最新主要文献でみる 脳神経外科学レビュー（8 脳血管障害と遺伝子） (2019)
  • Author(s): 宮脇哲（監修 新井一 齊藤延人 若林俊彦）
  • Total Pages: 382
  • Publisher: 総合医学社
  • ISBN: 488378679X