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Pathogenesis of focal cortical dysplasia: possible mechanistic implification of somatic mutations

Research Project

Project/Area Number 25640027
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Nerve anatomy/Neuropathology
Research InstitutionNiigata University

Principal Investigator

KAKITA Akiyoshi  新潟大学, 脳研究所, 教授 (80281012)

Co-Investigator(Kenkyū-buntansha) TAKEI Nobuyuki  新潟大学, 脳研究所, 准教授 (70221372)
Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsてんかん / 脳神経疾患 / 皮質異形成 / 体細胞変異 / 外科病理 / 神経病理学
Outline of Final Research Achievements

We explore the possible involvement of somatic mutations in focal cortical dysplasia (FCD) Type IIb. We performed whole exome sequencing using brain and blood samples from nine of the FCD Type IIb subjects. Somatic MTOR mutations were identified. The effect of MTOR mutations on mTOR kinase signaling was evaluated. We identified four lesion-specific somatic MTOR mutations in six of 13 (46%) individuals with FCD Type IIb showing mutant allele rates of 1.11 - 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD Type IIb brain tissues with MTOR mutations was clearly elevated compared with control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. We found low-prevalence somatic mutations in MTOR in FCD Type IIb, indicating that activating somatic mutations in MTOR cause FCD Type IIb.

Report

(3 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • Research Products

    (28 results)

All 2015 2014 2013 Other

All Journal Article (11 results) (of which Peer Reviewed: 9 results,  Acknowledgement Compliant: 1 results) Presentation (14 results) (of which Invited: 6 results) Book (3 results)

  • [Journal Article] Characteristic p57/Kip2 immunoreactivity of balloon cells in focal cortical dysplasia.2015

    • Author(s)
      Kimura T, Kitaura H, Masuda H, Kameyama S, Saito Y, Otsuki T, Nakazawa A, Morota N, Yamamoto T, Iida K, Takahashi H, Kakita A.
    • Journal Title

      Neuropathology

      Volume: 00 Issue: 5 Pages: 000-000

    • DOI

      10.1111/neup.12199

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Two siblings with cortical dysplasias: focal cortical dysplasia and hemimegalencephaly: clinicoencephalographic features.2015

    • Author(s)
      Fukasawa T, Kubota T, Negoro T, Maruyama S, Honda R, Saito Y, Ito M, Kakita A, Sugai K, Otsuki T, Natsume J, Watanabe K.
    • Journal Title

      Pediatr Int

      Volume: 00 Pages: 000-000

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] てんかん外科病理:最新の国際分類について.2015

    • Author(s)
      柿田明美
    • Journal Title

      最新医学

      Volume: 00 Pages: 000-000

    • Related Report
      2014 Annual Research Report
  • [Journal Article] 結節性硬化症.2015

    • Author(s)
      北浦弘樹、柿田明美.
    • Journal Title

      Epilepsy

      Volume: 8 Pages: 74-76

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Histopathologic features of glia in human epileptogenic brain lesions2014

    • Author(s)
      柿田明美
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 54 Issue: 12 Pages: 1136-1138

    • DOI

      10.5692/clinicalneurol.54.1136

    • NAID

      130004921158

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 小児てんかん原性病巣の外科病理.2014

    • Author(s)
      柿田明美
    • Journal Title

      脳発達

      Volume: 46 Pages: 413-417

    • NAID

      130005005740

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oligodendroglioma (WHO grade I) in a young epilepsy patient: a specific entity lying within the spectrum of dysembryoplastic neuroepithelial tumor?2013

    • Author(s)
      Takahashi H, Kakita A, Tomikawa M, Okamoto K, Kameyama S
    • Journal Title

      Neuropathology

      Volume: 44 Issue: 6 Pages: 645-651

    • DOI

      10.1111/neup.12026

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Electrocorticographic–Histopathologic Correlations Implying Epileptogenicity of Dysembryoplastic Neuroepithelial Tumor2013

    • Author(s)
      Kagawa K, Iida K, Kakita A, Katagiri M, Nishimoto T, Hashizume A, Kiura Y, Hanaya R, Sugiyama K, Arihiro K, Arita K, Kurisu K
    • Journal Title

      Neurologia medico-chirurgica

      Volume: 53 Issue: 10 Pages: 676-687

    • DOI

      10.2176/nmc.oa2012-0420

    • NAID

      10031191637

    • ISSN
      0470-8105, 1349-8029
    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Surgical pathologic features of cerebral cortical lesions taken from 600 patients with intractable epilepsy.2013

    • Author(s)
      Kakita A
    • Journal Title

      Brain Dev

      Volume: 35 Issue: 8 Pages: 793-801

    • DOI

      10.1016/j.braindev.2013.03.008

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Optical imaging of human epileptogenic tissues in vitro.2013

    • Author(s)
      Kitaura H, Kakita A
    • Journal Title

      Neuropathology

      Volume: 33 Issue: 4 Pages: 469-474

    • DOI

      10.1111/neup.12017

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Suppressed Expression of Autophagosomal Protein LC3 in Cortical Tubers of2013

    • Author(s)
      Miyahara H, Natsumeda M, Shiga A, Aoki H, Toyoshima Y, Zheng Y, Takeuchi R,
    • Journal Title

      Brain Pathol.

      Volume: 23 Issue: 3 Pages: 254-262

    • DOI

      10.1111/j.1750-3639.2012.00634.x

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Different mechanism of epileptogensis in subiculum and dentate gyrus in mesial temporal lobe epilepsy: an in vitro optical imaging study of resected human hippocampus.2014

    • Author(s)
      Kitaura H, Shirozu H, Shimizu H, Sonoda M, Murakami H, Masuda H, Takahashi H, Kameyama S, Kakita A.
    • Organizer
      Society for Neuroscience
    • Place of Presentation
      Walter E. Washington Convention Center, Washington DC, USA
    • Year and Date
      2014-11-15 – 2014-11-19
    • Related Report
      2014 Annual Research Report
  • [Presentation] てんかん焦点の病理2014

    • Author(s)
      柿田明美.
    • Organizer
      第48回日本てんかん学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-10-02 – 2014-10-03
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 視床下部過誤腫の生検組織スライス標本を用いた生理学的・薬理学的研究.2014

    • Author(s)
      園田真樹、北浦弘樹、伊藤陽祐、白水洋史、増田浩、柿田明美、亀山茂樹
    • Organizer
      第48回日本てんかん学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-10-02 – 2014-10-03
    • Related Report
      2014 Annual Research Report
  • [Presentation] 内側側頭葉てんかん患者の海馬萎縮:VBMによるMRI解析と病理所見との比較研究2014

    • Author(s)
      伊藤陽祐、増田浩、白水洋史、村上博淳、園田真樹、亀山茂樹、北浦弘樹、高橋均、柿田明美.
    • Organizer
      第48回日本てんかん学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-10-02 – 2014-10-03
    • Related Report
      2014 Annual Research Report
  • [Presentation] 視床下部過誤腫におけるてんかん原性のin vitro 脳スライス標本を用いた検討.2014

    • Author(s)
      北浦弘樹、園田真樹、清水宏、白水洋史、伊藤陽祐、増田浩、高橋均、亀山茂樹、柿田明美.
    • Organizer
      第55回日本神経病理学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-06-05 – 2014-06-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] 内側側頭葉てんかん患者の海馬硬化組織特異的な酸化損傷タンパクの同定.2014

    • Author(s)
      古川絢子、柿田明美、千葉陽一、樋口善博、高橋均、亀山茂樹、島田厚良.
    • Organizer
      第55回日本神経病理学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-06-05 – 2014-06-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] 内側側頭葉てんかんにおける臨床病理学的研究.2014

    • Author(s)
      塩谷彩子、大槻泰介、佐々木征行、佐藤典子、柿田明美、齊藤祐子.
    • Organizer
      第55回日本神経病理学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-06-05 – 2014-06-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] L1CAM遺伝子変異を伴う伴性劣性遺伝性水頭症の胎児例.2014

    • Author(s)
      清水宏、花岡仁一、金村米博、山崎麻美、田澤立之、高橋均、柿田明美.
    • Organizer
      第55回日本神経病理学会.
    • Place of Presentation
      東京
    • Year and Date
      2014-06-05 – 2014-06-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] 限局性皮質形成異常によるてんかん患者の発作頻度の特徴について.2014

    • Author(s)
      跡部真人,須貝研司,石山昭彦,齋藤貴志,斎藤義朗,小牧宏文,中川栄二,佐々木征行,高橋章夫,大槻泰介,伊藤雅之,柿田明美.
    • Organizer
      第56回日本小児神経学会.
    • Place of Presentation
      浜松
    • Year and Date
      2014-05-29 – 2014-05-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] てんかんの病理

    • Author(s)
      柿田明美
    • Organizer
      第37回日本てんかん外科学会
    • Place of Presentation
      大阪
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 難治てんかん原性病巣の病態病理:外科標本の解析

    • Author(s)
      柿田明美
    • Organizer
      奈良てんかん懇話会
    • Place of Presentation
      奈良
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] てんかんの病理

    • Author(s)
      柿田明美
    • Organizer
      西新潟中央病院てんかんセンター 夏季セミナー
    • Place of Presentation
      新潟
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] てんかん外科病理学の実際 ―ビジュアルにみる―

    • Author(s)
      柿田明美
    • Organizer
      第9回 日本てんかん学会近畿地方会
    • Place of Presentation
      大津
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 小児てんかん原性病巣の外科病理 ―ビジュアルに示す―

    • Author(s)
      柿田明美
    • Organizer
      第55回日本小児神経学会総会学術研究会
    • Place of Presentation
      大分
    • Related Report
      2013 Research-status Report
    • Invited
  • [Book] 臨牀てんかん学2015

    • Author(s)
      柿田明美(分担執筆).(編集:兼本浩祐、丸 栄一、池田昭夫、川合謙介)
    • Publisher
      医学書院
    • Related Report
      2014 Annual Research Report
  • [Book] 稀少難治てんかん診療マニュアル2013

    • Author(s)
      柿田明美(分担執筆)。編集:大槻泰介,須貝研司,小国弘量,井上有史,永井利三郎
    • Total Pages
      170
    • Publisher
      診断と治療社
    • Related Report
      2013 Research-status Report
  • [Book] てんかん専門医ガイドブック.―てんかんにかかわる医師のための基礎知識―2013

    • Author(s)
      柿田明美(分担執筆)。編集:日本てんかん学会
    • Total Pages
      303
    • Publisher
      診断と治療社
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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