Molecular analyses of glaucoma-associated mutations in OPTN gene and retinal blood flow

• Project/Area Number: 24791885
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: 独立行政法人国立病院機構(東京医療センター臨床研究センター)
• Principal Investigator: MINEGISHI Yuriko 独立行政法人国立病院機構(東京医療センター臨床研究センター), 分子細胞生物学研究部, 研究員 (20621832)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 緑内障 / 家族性緑内障 / 遺伝子変異 / オプチニューリン / Optineurin / E50K / 正常眼圧緑内障 / 遺伝性疾患 / 神経変性疾患 / E50K変異 / 緑内障変異 / 分子細胞生物学

Research Abstract

The optineurin (OPTN) E50K mutation was first identified in familial glaucoma. We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes. Further phenotypic analysis of these E50K-tg mice revealed the abnormal localization of E50K mutant protein deposits in retina, indicating a mutant protein aggregation/insolubility. Neurons derived from induced pluri potent stem cells (iPSCs) from E50K-glaucoma patients exhibited increased insolubilized OPTN. The E50K mutant strongly interacted with TBK1 and treatment with a TBK1 inhibitor abrogated the aberrant insolubility of E50K. Here, we delineated the underlying pathoetiology of E50K-glaucoma associating with mutant protein aggregation.

Research Products

• [Journal Article] Enhanced Optineurin E50 K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. (2013)
  • Author(s): Minegishi Y, Seki T, Yuasa S, Fukuda K, Iwata T, et al
  • Journal Title: Hum Mol Genet. Volume: 22 Issue: 17 Pages: 3559-3367
  • DOI: 10.1093/hmg/ddt210
  • Peer Reviewed
• [Presentation] オプチニューリンのアミノ酸 E50K 変異による遺伝性緑内障の発症機序 (2014)
  • Author(s): 峯岸ゆり子, 岩田岳
  • Organizer: 第19回東北眼疾患病態研究会
  • Place of Presentation: 仙台
  • Year and Date: 2014-05-19
  • Invited
• [Presentation] Etiologic dynamics of optineurin E50K mutant in iPSC from open angle glaucoma patient (2013)
  • Author(s): Minegishi, Y., Iwata, T
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2013-11-13
• [Presentation] Distinct protein complex formation evokes insolubility of OPTN and mislocalization in iPSC-derived neural cells from E50K-POAG patients (2013)
  • Author(s): Minegishi, Y., Iejima, D., Kobayashi, H., Chi., ZL., Kawase, K., Yamamoto, T., Seki, T., Yuasa, S., Fukuda, K., Iwata, T
  • Organizer: ARVO2013
  • Place of Presentation: Seattle, WA, USA
  • Year and Date: 2013-05-05
• [Presentation] 緑内障原因遺伝子オプチニューリンとE50K 変異によるタンパクの不溶化と病態発症との関連 (2013)
  • Author(s): 峯岸ゆり子, 家島大輔, 小林宏明, 池在龍, 川瀬和秀, 山本哲也, 関倫久, 湯浅慎介, 福田恵一, 岩田岳
  • Organizer: 第17回眼科分子生物学研究会
  • Place of Presentation: 静岡
  • Year and Date: 2013-02-24
• [Presentation] オプチニューリン E50K 変異体による正常眼圧緑内障の病態機序の解明 (2012)
  • Author(s): 峯岸ゆり子, 小林宏明, 家島大輔, 岩田岳
  • Organizer: 第5回 Retinal Research Meeting
  • Place of Presentation: 東京
  • Year and Date: 2012-12-08
• [Presentation] Comparative functional analysis of optineurin and its glaucoma-related mutant E50K by mammalian cell-based LC-MS/MS proteomics (2012)
  • Author(s): Minegishi, Y., Kobayashi, H., Iwata, T
  • Organizer: XX Biennial Meeting of the International Society for Eye Research
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-07-25
• [Presentation] Aberrant accumulation of glaucoma-associated OPTN E50K mutant protein potentiates the glaucomatous retinal vulnerability (2012)
  • Author(s): Minegishi, Y., Iwata, T
  • Organizer: XX Biennial Meeting of the International Society for Eye Research
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-07-23
• [Presentation] Etiologic dynamics of optineurin E50K mutant in iPSC from open angle glaucoma patient.
  • Author(s): Minegishi, Y., Iwata, T.
  • Organizer: Neuroscience 2013
  • Place of Presentation: サンディエゴ、 アメリカ。
• [Presentation] オプチニューリンのアミノ酸E50K変異による遺伝性緑内障の発症機序
  • Author(s): 峯岸ゆり子、 岩田岳
  • Organizer: 第19回東北眼疾患病態研究会
  • Place of Presentation: 仙台、 日本。
  • Invited
• [Presentation] Aberrant accumulation of glaucoma-associated OPTN E50K mutant protein potentiates the glaucomatous retinal vulnerability
  • Author(s): Minegishi, Y., Iwata
  • Organizer: XX Biennial Meeting of the International Society for Eye Research
  • Place of Presentation: ベルリン、ドイツ
• [Presentation] Comperative functional analysis of optineurin and its glaucoma-related mutant E50K by mammalian cell-based LC-MS/MS proteomics
  • Author(s): Minegishi, Y., Kobayashi, H., Iwata
  • Organizer: XX Biennial Meeting of the International Society for Eye Research
  • Place of Presentation: ベルリン、ドイツ
• [Presentation] オプチニューリンE50K変異体による正常眼圧緑内障の病態機序の解明
  • Author(s): 峯岸ゆり子、小林宏明、家島大輔、岩田岳
  • Organizer: The 5th Retinal Research Meeting
  • Place of Presentation: 東京
• [Presentation] 緑内障原因遺伝子オプチニューリンとE50K変異によるタンパクの不溶化と病態発症との関連
  • Author(s): 峯岸ゆり子、家島大輔、小林宏明、池在龍、川瀬和秀、山本哲也、関倫久、湯浅慎介、福田恵一、岩田岳
  • Organizer: 第17回眼科分子生物学研究会
  • Place of Presentation: 静岡
• [Presentation] Distinct protein complex formation evokes insolubility of OPTN and mislocalization in iPSC-derived neural cells from E50K-POAG patients
  • Author(s): Minegishi, Y., Iejima, D., Kobayashi, H., Chi1., ZL., Kawase, K., Yamamoto, T., Seki, T., Yuasa, S., Fukuda, K., Iwata, T
  • Organizer: ARVO2013 Annual Meeting
  • Place of Presentation: シアトル、アメリカ
• [Book] 日本人のヒット論文-本音で語る苦労話-第5回 オプチニューリン E50K 変異による遺伝性緑内障発症の機序『Retina Medicine』(中澤徹編) (2014)
  • Author(s): 峯岸ゆり子
  • Publisher: 先端医学社
• [Book] Retina Medicine (2014)
  • Author(s): 峯岸ゆり子
  • Total Pages: 111
  • Publisher: 先端医学社
• [Remarks] 東京医療センター 臨床研究センター 感覚器センター 分子細胞生物学研究部
  • URL: http://www.kankakuki.go.jp/lab_e.html
• [Remarks] 東京医療センター 臨床研究センター 感覚器センター 分子細胞生物学研究部
  • URL: http://www.kankakuki.go.jp/lab_e.html