Elucidation of molecular mechanism of moyamoya disease for prophylaxis

• Project/Area Number: 25893104
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hygiene and public health
• Research Institution: Kyoto University
• Principal Investigator: KOBAYASHI Hatasu 京都大学, 医学(系)研究科(研究院), 講師 (70542091)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: もやもや病 / RNF213 / iPS細胞 / 血管内皮細胞 / 動物モデル / mysterin / トランスジェニックマウス / 細胞分裂異常

Outline of Final Research Achievements

Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The Mysterin (RNF213) R4810K polymorphism increases susceptibility to MMD. Mysterin R4810K reduced angiogenic activities of induced pluripotent stem cell-derived vascular endothelial cells (iPSECs) from patients with MMD. Overexpression of Mysterin R4810K inhibited angiogenic activity of human umbilical vein endothelial cells, while overexpression of Mysterin wild type (WT) did not. In addition, Mysterin R4810K was demonstrated to induce mitotic abnormalities and increased risk of genomic instability. To confirm the anti-angiogenic effect of Mysterin upregulation in vivo, vascular endothelial cell- or smooth muscle cell-specific Mysterin R4757K (R4810K orthologue) or WT transgenic mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in endothelial cell-specific Mysterin R4757K transgenic mice, while it was not suppressed in other mice.

Research Products

• [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] 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] 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] もやもや病とRNF213遺伝子 (2014)
  • Author(s): 小林果、人見敏明、小泉昭夫
  • Journal Title: 分子脳血管病 Volume: 13 Pages: 54-56
• [Journal Article] Temporal trend and age-dependent serum concentration of phenolic organohalogen contaminants in Japanese men during 1989-2010. (2014)
  • Author(s): Fuiii, Y. ; Harada, K. H. ; Hitomi, T. ; Kobayashi, H. ; Koizumi, A. ; Haraguchi, K
  • Journal Title: Environ Pollut Volume: 185 Pages: 228-233
  • DOI: 10.1016/j.envpol.2013.11.002
  • 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] Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients. (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: 438(1): Issue: 1 Pages: 13-19
  • DOI: 10.1016/j.bbrc.2013.07.004
  • 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] 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] 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] もやもや病感受性遺伝子の特定 (2013)
  • Author(s): 小林果、人見敏明, 小泉昭夫
  • Journal Title: Bio Clinica Volume: 28 Issue: 6 Pages: 87-91
  • DOI: 10.1038/jhg.2013.20
  • Peer Reviewed
• [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
• [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 Pages: 1456-1457
• [Presentation] もやもや病および脊髄小脳変性症36型の原因遺伝子の同定および機能解析 (2015)
  • Author(s): 小林果
  • Organizer: 第85回日本衛生学会学術総会
  • Place of Presentation: 和歌山市
  • Year and Date: 2015-03-26 – 2015-03-28
  • 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: 和歌山市
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 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 (2015)
  • Author(s): 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
  • Organizer: 第85回日本衛生学会学術総会
  • Place of Presentation: 和歌山市
  • Year and Date: 2015-03-26 – 2015-03-28
• [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: 岡山市
  • Year and Date: 2014-05-25 – 2014-05-27
• [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回分子環境予防医学研究会
  • Place of Presentation: 和歌山県民文化会館（和歌山県）