Molecular pathology of moyamoyta disease and its translational research toward prevention and drug development

• Project/Area Number: 25253047
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Epidemiology and preventive medicine
• Research Institution: Kyoto University
• Principal Investigator: KOIZUMI Akio 京都大学, 医学(系)研究科(研究院), 教授 (50124574)
• Co-Investigator(Kenkyū-buntansha): SONE Masakatsu 京都大学, 大学院医学研究科, 特定准教授 (40437207) ; MIYAMOTO Susumu 京都大学, 大学院医学研究科, 教授 (70239440) ; TAKAGI Yasushi 京都大学, 大学院医学研究科, 准教授 (40312227) ; HABU Toshiyuki 武庫川女子大学, 生活環境学部, 准教授 (70346071) ; YAMAZAKI Satoru 独立行政法人国立循環器病研究センター, 細胞生物学部, 室長 (70348796) ; HARADA Koji 京都大学, 大学院医学研究科, 准教授 (80452340) ; HITOMI Toshiaki 聖マリアンナ医科大学, 医学部, 准教授 (90405275)
• Project Period (FY): 2013-10-21 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000); Fiscal Year 2015: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000); Fiscal Year 2014: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2013: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
• Keywords: 分子遺伝疫学 / 予防医学 / 社会医学 / 衛生学 / 医歯薬学

Outline of Final Research Achievements

We found that RNF213 is the susceptibility gene for moyamoya disease (MMD and its R4810K variant is the founder mutation among Asians. In the present project、we expanded the research in three fields. First, we investigated association of R4810K with coronary artery disease (CAD), which is often complicated with MMD and found strong association between RNF213 R4810K and CAD. In the transgenic animal study, overexpression of R4757K in endothelial cells (human R4810K orthologue) was found to inhibit angiogenesis in brain under the hypoxia. Finally, we found that a small molecule which inhibits ATPase activity by interacting with A module is a promising candidate for drug development.

Research Products

• [Journal Article] A new horizon of moyamoya disease and associated health risks explored through RNF213. (2016)
  • Author(s): Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S.
  • Journal Title: Environ Health Prev Med. Volume: 21(2) Issue: 2 Pages: 55-70
  • DOI: 10.1007/s12199-015-0498-7
  • NAID: 120005973383
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early onset of moyamoya syndrome in a Down syndrome patient with the genetic variant RNF213 p.R4810K (2015)
  • Author(s): Pin Fee Chong, Reina Ogata, Hatasu Kobayashi, Akio Koizumi, Ryutaro Kira
  • Journal Title: Brain Dev. Available Volume: Available online Issue: 8 Pages: 822-4
  • DOI: 10.1016/j.braindev.2014.12.006
  • Peer Reviewed
• [Journal Article] Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. (2015)
  • Author(s): Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Habu T, Takagi Y, Miyamoto S, Koizumi A.
  • Journal Title: J Am Heart Assoc. Volume: 30;4(7) Issue: 7
  • DOI: 10.1161/jaha.115.002146
  • Peer Reviewed / Open Access
• [Journal Article] The importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency (2015)
  • Author(s): Hitomi T, Matsuura N, Shigematsu Y, Okano Y, Shinozaki E, Kawai M, Kobayashi H, Harada KH, Koizumi A.
  • Journal Title: Journal of Genetics Volume: 94（1） Issue: 1 Pages: 147-150
  • DOI: 10.1007/s12041-015-0486-0
  • Peer Reviewed
• [Journal Article] Genetic Study of Intracranial Aneurysms (2015)
  • Author(s): Yan JX, Hitomi T, Takenaka K, Kato M, Kobayashi H, Okuda H, Harada KH, Koizumi A.
  • Journal Title: Stroke Volume: 46(3) Issue: 3 Pages: 620-626
  • DOI: 10.1161/strokeaha.114.007286
  • Peer Reviewed
• [Journal Article] An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka (2014)
  • Author(s): Nanayakkara, S., Senevirathna, S., Abeysekera, T., Chandrajith, R., Ratnatunga, N., Gunarathne, E., Yan, J., Hitomi, T., Muso, E., Komiya, T., Harada, K., Liu, W., Kobayashi, H., Okuda, H., Sawatari, H., Matsuda, F., Yamada, R., Watanabe, T., Miyataka, H., Himeno, S., Koizumi, A.
  • Journal Title: Journal of Occupational Health Volume: 56 Issue: 1 Pages: 28-38
  • DOI: 10.1539/joh.13-0172-OA
  • NAID: 130004848049
  • ISSN: 1341-9145, 1348-9585
  • Peer Reviewed
• [Journal Article] 1. Pcf1, a large subunit of CAF-1, required for maintenance of checkpoint kinase Cds1 activity (2014)
  • Author(s): Kunoh T and Habu T.
  • Journal Title: Springer Plus Volume: 3:30 Issue: 1 Pages: 1-8
  • DOI: 10.1186/2193-1801-3-30
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies no major founder variant in Caucasian moyamoya disease (2013)
  • Author(s): Liu W, Hitomi T, Kobayashi H, Koizumi A. et al.
  • Journal Title: J Genet Volume: 92(3) Issue: 3 Pages: 605-609
  • DOI: 10.1007/s12041-013-0304-5
  • Peer Reviewed
• [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2013)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
  • Journal Title: PNAS Volume: 111 Issue: 1 Pages: 273-278
  • DOI: 10.1073/pnas.1318547111
  • Peer Reviewed / Open Access
• [Journal Article] Rapid Progression of Unilateral Moyamoya Disease in a Patient with a Family History and an RNF213 Risk Variant (2013)
  • Author(s): Mineharu Y, Hitomi T, Kobayashi H Koizumi A. et al.
  • Journal Title: Cerebrovasc Dis Volume: 36(2) Issue: 2 Pages: 155-7
  • DOI: 10.1159/000352065
  • Peer Reviewed
• [Journal Article] The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) (2013)
  • Author(s): Hitomi T, Habu T, Kobayashi H, Okuda H, Harada KH, Osafune K, Taura D, Sone M, Asaka I, Ameku T, Watanabe A, Kasahara T, Sudo T, Shiota F, Hashikata H, Takagi Y, Morito D, Miyamoto S, Nakao K, Koizumi A
  • Journal Title: Biochem Biophys Res Commun. Volume: 439(4) Issue: 4 Pages: 419-426
  • DOI: 10.1016/j.bbrc.2013.08.067
  • Peer Reviewed
• [Journal Article] p31comet inactivates the chemically induced Mad2-dependent spindle assembly checkpoint and leads to resistance to anti-mitotic drugs (2013)
  • Author(s): Habu T and Matsumoto T.
  • Journal Title: Springer Plus Volume: 2:562 Issue: 1 Pages: 1-15
  • DOI: 10.1186/2193-1801-2-562
  • Peer Reviewed
• [Journal Article] もやもや病の遺伝子変異 (2013)
  • Author(s): 小林果、人見敏明、小泉昭夫
  • Journal Title: Clinical Neuroscience Volume: 31（12） Pages: 1147-1150
• [Journal Article] もやもや病感受性遺伝子mysterinにおける日中韓で共通な創始者多型と人類学的考察 (2013)
  • Author(s): 小泉昭夫、小林果
  • Journal Title: DNA多型 Volume: 21 Pages: 1-7
• [Presentation] もやもや病感受性多型RNF213遺伝子p.R4810Kによるangiogenesis抑制のin vitroおよびin vivoでの検討 (2015)
  • Author(s): 松田佳子、小林果、人見敏明、奥田裕子、塩井大智、原田浩二、峰晴陽平、高木康志、宮本享、小泉昭夫
  • Organizer: 第27回 日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場
  • Year and Date: 2015-10-30
• [Presentation] Mysterin/RNF213 p.R4810K変異からみたもやもや病の特徴 (2015)
  • Author(s): 峰晴陽平、高木康志、森本貴昭、松田佳子、小林果、人見敏明、原田浩二、宮本享、小泉昭夫
  • Organizer: 第27回 日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場
  • Year and Date: 2015-10-30
• [Presentation] 内頸動脈管径とRNF213遺伝子多型によるもやもや病の診断 (2015)
  • Author(s): 森本貴昭、峰晴陽平、坂井信幸、高木康志、人見敏明、小林果、谷正一、上野泰、今村博敏、藤堂謙一、松田佳子、小泉昭夫、宮本享
  • Organizer: 第27回 日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場
  • Year and Date: 2015-10-30
• [Presentation] In vitro and in vivo evidence on inhibition of angiogenesis by the Moyamoya susceptible gene and its mutation, RNF213 R4810K (2015)
  • Author(s): Koizumi A, Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Takagi Y, Miyamoto S, Habu T.
  • Organizer: 4th International Moyamoya Meeting Berlin
  • Place of Presentation: Berlin
  • Year and Date: 2015-07-02
  • Int'l Joint Research / Invited
• [Presentation] 血管内皮特異的mysterin変異体Tgマウスにおける低酸素による脳angiogenesis誘導の低下 (2015)
  • Author(s): 小林果、奥田裕子、塩井大智、松田佳子、人見敏明、原田浩二、小泉昭夫
  • Organizer: 第85回 日本衛生学会学術総会
  • Place of Presentation: アバローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 血管平滑筋特異的mysterin変異体Tgマウスにおける低酸素誘導性肺arteriogenesisの抑制 (2015)
  • Author(s): 小林果、奥田裕子、塩井大智、松田佳子、人見敏明、原田浩二、小泉昭夫
  • Organizer: 第85回 日本衛生学会学術総会
  • Place of Presentation: アバローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] MysterinはIFNβによる抗血管形成シグナル経路のメディエーターとして働く (2015)
  • Author(s): 人見敏明、小林果、奥田裕子、曽根正勝、田浦大輔、原田浩二、土生敏行、小泉昭夫
  • Organizer: 第85回 日本衛生学会学術総会
  • Place of Presentation: アバローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] もやもや病感受性変異体は有糸分裂異常によりゲノム不安定性を誘導する (2014)
  • Author(s): 人見敏明、小林果、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第84回 日本衛生学会学術総会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] もやもや病特異的iPS細胞由来血管内皮細胞における血管形成能の低下 (2014)
  • Author(s): 小林果、人見敏明、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第84回 日本衛生学会学術総会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Moyamoya 病のミニレビューと今後の研究の方向 (2014)
  • Author(s): 小泉昭夫、小林果、原田浩二、人見敏明
  • Organizer: 第13回 分子予防環境医学研究会
  • Place of Presentation: 和歌山県立文化会館
• [Presentation] Mysterin遺伝子のR4810K多型はもやもや病特異的iPS細胞由来血管内皮細胞においてSecurinの発現抑制を介して血管形成能を低下させる (2014)
  • Author(s): 小林果、人見敏明、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第13回 分子予防環境医学研究会
  • Place of Presentation: 和歌山県立文化会館
• [Presentation] もやもや病感受性変異体Mysterin R4810Kは有糸分裂異常によりゲノム不安定性を誘導する (2014)
  • Author(s): 人見敏明、小林果、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第13回 分子予防環境医学研究会
  • Place of Presentation: 和歌山県立文化会館
• [Presentation] The E3 ligase Asb2 regulates cardiac development through targeting Smad9 for proteasomal degradation. (2014)
  • Author(s): Kyung-Duk Min
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム
• [Remarks] 京都大学大学院医学研究科環境衛生学分野HP
  • URL: http://hes.med.kyoto-u.ac.jp/
• [Remarks] 京都大学大学院医学研究科環境衛生学分野ＨＰ
  • URL: http://hes.med.kyoto-u.ac.jp/
• [Remarks] 京都大学 大学院医学研究科 環境衛生学分野
  • URL: http://130.54.180.142/index.html