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The treatment strategy for HIBCH deficiency targeting mitochondrial dysfunction

Research Project

Project/Area Number 15K09610
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionInstitute for Developmental Research, Aichi Human Service Center

Principal Investigator

Yamada Kenichiro  愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 主任研究員 (30291173)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsHIBCH欠損症 / ミトコンドリア / バリン代謝 / グルタチオン
Outline of Final Research Achievements

In HIBCH deficiency, methacrylyl-CoA, an intermediate product of valine metabolism, accumulates in mitochondria of multiple tissues. Methacrylyl-CoA reacts with thiol compounds (e.g., cysteamine, cysteine and reduced glutathione (GSH)) and essential cysteine residues of mitochondrial enzymes, including multiple respiratory chain enzymes and pyruvate dehydrogenase complex, and reduces their activities. This leads to cell damage, especially in the basal ganglia, by dramatically decreasing the cellular reduction state and reducing ATP production. In this study, we analyzed patient’s lymphoblasts, and found that the survival rate of patient’s lymphoblasts decreased during culture with a low glucose medium. Using this condition, we evaluated the therapeutic effect (maintaining of the survival rate) of candidate drugs for HIBCH deficiency. We found that one candidate drug that increases intracellular GSH levels restored the survival rate of patient lymphoblasts.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (23 results)

All 2017 2016 2015

All Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (18 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice.2017

    • Author(s)
      Suzuki K, Yamada K, Fukuhara Y, Tsuji A, Shibata K, Wakamatsu N.
    • Journal Title

      PLoS One

      Volume: 12(6) Issue: 6 Pages: 1-17

    • DOI

      10.1371/journal.pone.0180279

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter.2017

    • Author(s)
      Fukushi D, Kurosawa K, Suzuki Y, Suzuki K, Yamada K, Watanabe S, Yokochi K, Wakamatsu N.
    • Journal Title

      Am J Med Genet A

      Volume: 173(8) Issue: 8 Pages: 2201-2209

    • DOI

      10.1002/ajmg.a.38313

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS).2017

    • Author(s)
      Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, Wakamatsu N.
    • Journal Title

      Oncotarget

      Volume: 8(28) Issue: 28 Pages: 45470-45483

    • DOI

      10.18632/oncotarget.17566

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel mutation in HPRT1 causing a splicing error with multiple variations.2017

    • Author(s)
      Baba S, Saito T, Yamada Y, Takeshita E, Nomura N, Yamada K, Wakamatsu N, Sasaki M.
    • Journal Title

      Nucleosides Nucleotides Nucleic Acids

      Volume: 36 Issue: 1 Pages: 1-6

    • DOI

      10.1080/15257770.2016.1163381

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion2015

    • Author(s)
      Yamada K, Aiba K, Kitaura Y, Kondo Y, Nomura N, Nakamura Y, Fukushi D, Murayama K, Shimomura Y, Pitt J, Yamaguchi S, Yokochi K, Wakamatsu N
    • Journal Title

      Journal of Medical Genetics

      Volume: 52 Issue: 10 Pages: 691-698

    • DOI

      10.1136/jmedgenet-2015-103231

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] チアミンとビオチン併用療法を行ったBiotin-responsive Basal Ganglia Diseaseの1例.2017

    • Author(s)
      友松典子, 榊原崇文, 山田憲一郎, 若松延昭, 嶋緑倫
    • Organizer
      第120回日本小児科学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Two female patients with Xq27.3q28 deletion and skewed X-inactivation display similar phenotypes as Hunter syndrome.2017

    • Author(s)
      Katoh K, Aiba K, Fukushi D, Suzuki Y, Yamada K, Wakamatsu N
    • Organizer
      XXIII World Congress of Neurology (WCN 2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 疾患モデルマウスを用いたチアミントランスポーター(SLC19A3)欠損症の病態解明.2017

    • Author(s)
      若松延昭, 鈴木香, 辻愛,柴田克己, 山田憲一郎
    • Organizer
      平成29年度香川県医学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Clinical and molecular genetic characterization of two siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter.2017

    • Author(s)
      Fukushi D, Kurosawa K, Suzuki Y, Suzuki K, Yamada K, Watanabe S, Yokochi K, Wakamatsu N
    • Organizer
      日本人類遺伝学会第62回大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] モデルマウスを用いたSLC19A3欠損症の病態解明とチアミン治療の検証.2017

    • Author(s)
      山田憲一郎, 鈴木 香, 福原弥生, 辻愛, 柴田克己, 若松延昭
    • Organizer
      2017年度 生命化学系学会合同年次大会 ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] メトホルミンがPIK3CA-related overgrowth spectrum(PROS)患者由来細胞におよぼす治療効果.2017

    • Author(s)
      鈴木康予, 榎戸靖, 山田憲一郎, 稲葉美枝, 花田直樹, 森下剛, 水野誠司, 若松延昭
    • Organizer
      2017年度生命科学系学会合同年次大会 ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] バリン代謝異常症の病態解明と治療へのアプローチ.2017

    • Author(s)
      山田憲一郎
    • Organizer
      発達障害研究所公開セミナー2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] バリン代謝異常症の病態解明と診断及び治療戦略.2016

    • Author(s)
      山田憲一郎
    • Organizer
      日本薬学会 東海支部 特別講演会
    • Place of Presentation
      名古屋
    • Year and Date
      2016-01-15
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] PIK3CA-related overgrowth spectrum (PROS)の1症例.2015

    • Author(s)
      鈴木康予, 水野誠司, 榎戸 靖, 山田憲一郎, 稲葉美枝, 村松友佳子, 花田直樹, 森下剛, 若松延昭
    • Organizer
      第27回日本整形外科学会骨系統疾患研究会
    • Place of Presentation
      岐阜
    • Year and Date
      2015-12-05
    • Related Report
      2015 Research-status Report
  • [Presentation] ヒトECHS1の生化学的解析と軽症型ECHS1欠損症の病態解明2015

    • Author(s)
      山田憲一郎、相場佳織、北浦靖之、近藤雄介、野村紀子、中村勇治、福士大輔、村山圭、下村吉治、James Pitt、山口清次、横地健治、若松延昭
    • Organizer
      第88回日本生化学会大会、第38回日本分子生物学会年会 合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-03
    • Related Report
      2015 Research-status Report
  • [Presentation] PIK3CA-related overgrowth spectrum (PROS)の病態解明.2015

    • Author(s)
      鈴木康予, 榎戸靖, 山田憲一郎, 花田直樹, 森下剛, 水野誠司, 若松延昭
    • Organizer
      第88回日本生化学会大会、第38回日本分子生物学会年会 合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-03
    • Related Report
      2015 Research-status Report
  • [Presentation] 軽症Short-chain enoyl-CoA hydratase (ECHS1)欠損症の生化学的解析:診断に有効な化合物の同定2015

    • Author(s)
      若松延昭、山田憲一郎、北浦靖之、近藤雄介、野村紀子、村山圭、山口清次、下村吉治、横地健治、James Pitt
    • Organizer
      第57回日本先天代謝異常学会総会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] Biotin-Responsive Basal Ganglia Disease(BBGD)と診断した幼児例.2015

    • Author(s)
      榊原崇文, 高木久美子, 越智聡史, 竹下佳弘, 山田憲一郎, 若松延昭, 嶋緑倫
    • Organizer
      第58回日本小児神経学会近畿地方会
    • Place of Presentation
      大阪
    • Year and Date
      2015-10-24
    • Related Report
      2015 Research-status Report
  • [Presentation] SF3B4の欠失が見られるNager症候群の1症例.2015

    • Author(s)
      福士大輔, 水野誠司, 稲葉美枝, 鈴木香, 野村紀子, 鈴木康予, 山田憲一郎, 若松延昭
    • Organizer
      日本人類遺伝学会第60回大会
    • Place of Presentation
      東京
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Leigh disease and the valine pathway.2015

    • Author(s)
      Pitt J, Peters H, Yaplito-Lee J, Boneh A, Ferdinandusse S, Ruiter J, Wanders RJA, Kok F, Boy R, Korman SH, Fitzsimons PE, Crushell E, Hughes J, Yamaguchi S, Goto Y, Wakamatsu N, Yamada K, Yokochi K, Chen BC, Ngu LH
    • Organizer
      Annual Symposium 2015, Society for the Study of Inborn Errors of Metabolism
    • Place of Presentation
      Lyon, France
    • Year and Date
      2015-09-04
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 著しい下肢の過成長と部分的皮下脂肪組織の増殖を呈するPROS(PIK3CA-related Overgrowth Spectrum)の1例.2015

    • Author(s)
      水野誠司, 榎戸靖, 森下剛, 花田直樹, 山田憲一郎, 若松延昭
    • Organizer
      第55回日本先天異常学会
    • Place of Presentation
      横浜
    • Year and Date
      2015-07-25
    • Related Report
      2015 Research-status Report
  • [Presentation] PIK3CA-related overgrowth spectrum(PROS)の1症例2015

    • Author(s)
      鈴木康予,榎戸 靖,山田憲一郎,若松延昭,水野誠司,花田直樹,森下 剛
    • Organizer
      第103回東海臨床遺伝・代謝懇話会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-06-30
    • Related Report
      2015 Research-status Report
  • [Presentation] Clinical and biochemical characterization of patients with HIBCH deficiency.2015

    • Author(s)
      Wakamatsu N, Yamada K, Naiki M, Hoshino S, Kitaura Y, Kondo Y, Nomura N, Kimura R, Fukushi D, Yamada Y, Shimozawa N, Yamaguchi S, Shimomura Y, Miura K
    • Organizer
      第56回日本神経学会学術大会
    • Place of Presentation
      新潟
    • Year and Date
      2015-05-20
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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