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Elucidation of the molecular pathogenesis of mitochondrial disease

Research Project

Project/Area Number 16K09973
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionJuntendo University (2018)
Saitama Medical University (2016-2017)

Principal Investigator

Kishita Yoshihito  順天堂大学, 医学(系)研究科(研究院), 助教 (20634398)

Research Collaborator OKAZAKI Yasushi  
OHTAKE Akira  
MURAYAMA Kei  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsミトコンドリア / ミトコンドリア病 / 疾患原因遺伝子 / 遺伝性疾患 / アクチン / 疾患遺伝子
Outline of Final Research Achievements

Mitochondrial diseases are inherited metabolic diseases that occur when mitochondria fail to produce enough energy. In the field of pediatrics, causes of mitochondrial diseases and affected organs are particularly diverse, and the mechanism of pathogenesis may differ depending on the causative gene. To elucidate the pathogenic mechanism of mitochondrial diseases, I analyzed the molecular basis of mitochondrial diseases and searched for novel disease-causing genes. I focused on filamin genes that have been identified by previous whole exome sequencing. I have seen the abnormality of actin organization in filamin deficient cells. I have reported C1QBP and TOP3A as novel disease-causing genes.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリア病は先天代謝異常症のなかで最も患者数の多い疾患であるが、現在までにミトコンドリア病の有効な治療法が確立されておらず、また発症原因やその分子メカニズムも十分に明らかになっていない。基盤的な分子メカニズムの理解は創薬や治療法開発に不可欠な要素であるが、本研究では新たな疾患発症メカニズムの一端を明らかにすることができた。疾患の基盤的分子メカニズムの理解が今後、創薬や治療の分子標的を見出す研究へと展開されることが期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (21 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (11 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 11 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (9 results) (of which Int'l Joint Research: 7 results)

  • [Int'l Joint Research] Helmholtz Zentrum Munchen(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Mitochondrial complex deficiency by novel compound heterozygous TMEM70 variants and correlation with developmental delay, undescended testicle, and left ventricular noncompaction in a Japanese patient: A case report2019

    • Author(s)
      Hirono Keiichi、Ichida Fukiko、Nishio Natsuhito、Ogawa-Tominaga Minako、Fushimi Takuya、Feichtinger Rene′ G.、Mayr Johannes A.、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Ohtake Akira、Murayama Kei
    • Journal Title

      Clinical Case Reports

      Volume: 7 Issue: 3 Pages: 553-557

    • DOI

      10.1002/ccr3.2050

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background.2019

    • Author(s)
      Imai-Okazaki A, Kishita Y, Kohda M, Mizuno Y, Fushimi T, Matsunaga A, Yatsuka Y, Hirata T, Harashima H, Takeda A, Nakaya A, Sakata Y, Kogaki S, Ohtake A, Murayama K, Okazaki Y.
    • Journal Title

      Int J Cardiol

      Volume: 279 Pages: 115-121

    • DOI

      10.1016/j.ijcard.2019.01.017

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome.2019

    • Author(s)
      Borna NN, Kishita Y, Kohda M, Lim SC, Shimura M, Wu Y, Mogushi K, Yatsuka Y, Harashima H, Hisatomi Y, Fushimi T, Ichimoto K, Murayama K, Ohtake A, Okazaki Y.
    • Journal Title

      Neurogenetics

      Volume: 20(1) Issue: 1 Pages: 9-25

    • DOI

      10.1007/s10048-018-0561-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutations in TOP3A Cause a Bloom Syndrome-like Disorder2018

    • Author(s)
      Martin CA, Sarlos K, Logan CV, Thakur RS, Parry DA, Bizard AH, Leitch A, Cleal L, Ali NS, Al-Owain MA, Allen W, Altmuller J, Aza-Carmona M, Barakat BAY, Barraza-Garcia J, Begtrup A, Bogliolo M, Cho MT, Cruz-Rojo J, Dhahrabi HAM, Elcioglu NH; GOSgene, Gorman GS, Jobling R, Kesterton I, Kishita Y et al
    • Journal Title

      The American Journal of Human Genetics

      Volume: 103 Issue: 2 Pages: 221-231

    • DOI

      10.1016/j.ajhg.2018.07.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation2018

    • Author(s)
      Miyauchi Akihiko、Osaka Hitoshi、Nagashima Masako、Kuwajima Mari、Monden Yukifumi、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Murayama Kei、Ohtake Akira、Yamagata Takanori
    • Journal Title

      Brain and Development

      Volume: 40 Issue: 6 Pages: 498-502

    • DOI

      10.1016/j.braindev.2018.02.007

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Barth syndrome: Different approaches to diagnosis2018

    • Author(s)
      Imai-Okazaki A, Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Harashima H, Hirono K, Ichida F, Noguchi A, Yoshida M, Tokorodani C, Nishiuchi R, Takeda A, Nakaya A, Sakata Y, Murayama K, Ohtake A, & Okazaki Y
    • Journal Title

      Journal of Pediatrics

      Volume: 193 Pages: 256-260

    • DOI

      10.1016/j.jpeds.2017.09.075

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients2017

    • Author(s)
      Ogawa Erika、Shimura Masaru、Fushimi Takuya、Tajika Makiko、Ichimoto Keiko、Matsunaga Ayako、Tsuruoka Tomoko、Ishige Mika、Fuchigami Tatsuo、Yamazaki Taro、Mori Masato、Kohda Masakazu、Kishita Yoshihito、Okazaki Yasushi、Takahashi Shori、Ohtake Akira、Murayama Kei
    • Journal Title

      Journal of Inherited Metabolic Disease

      Volume: 40 Issue: 5 Pages: 685-693

    • DOI

      10.1007/s10545-017-0042-6

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies2017

    • Author(s)
      Feichtinger RG, Olahova M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H et al
    • Journal Title

      The American Journal of Human Genetics

      Volume: 101 Issue: 4 Pages: 525-538

    • DOI

      10.1016/j.ajhg.2017.08.015

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel mutation in TAZ causes mitochondrial respiratory chain disorder without cardiomyopathy2016

    • Author(s)
      Borna NN, Kishita Y, Ishikawa K, Nakada K, Hayashi JI, Tokuzawa Y, Kohda M, Nyuzuki H, Yamashita-Sugahara Y, Nasu T, Takeda A, Murayama K, Ohtake A, Okazaki Y
    • Journal Title

      J Hum Genet

      Volume: 62 Issue: 5 Pages: 539-547

    • DOI

      10.1038/jhg.2016.165

    • NAID

      40021210340

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dried blood spots for newborn screening allows easy determination of a high heteroplasmy rate in severe infantile cardiomyopathy2016

    • Author(s)
      Imai A, Kishita Y, Nakayama Y, Fujita S, Futatani T, Kohda M, Yatsuka Y, Nakaya A, Sakata Y, Murayama K, Ohtake A, Okazaki Y
    • Journal Title

      International Journal of Cardiology

      Volume: 221 Pages: 446-449

    • DOI

      10.1016/j.ijcard.2016.06.287

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] DNM1L-related encephalopathy in infancy with Leigh syndrome-like phenotype and suppression-burst.2016

    • Author(s)
      Zaha K, Matsumoto H, Itoh M, Saitsu H, Kato K, Kato M, Ogata S, Murayama K, Kishita Y, Mizuno Y, Kohda M, Nishino I, Ohtake A, Okazaki Y, Matsumoto N, Nonoyama S.
    • Journal Title

      Clinical Genetics

      Volume: 90 Issue: 5 Pages: 472-474

    • DOI

      10.1111/cge.12805

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] Association between mutations in genes encoding non-mitochondrial proteins and pathogenesis of mitochondrial diseases2018

    • Author(s)
      Kishita Y,Kohda M,Fushimi T, Yatsuka Y, Lim SC,Borna NN, Hirata T, Imai-Okazaki A,Matsunaga A, Shimura M, Tajika M, Kuranobu N, Ichimoto K, Harashima H,Murayama K,Ohtake A, Okazaki Y
    • Organizer
      AussieMit2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Homozygous mutation in MIC13 impairs cristae structure and causes mitochondrial DNA depletion syndrome2018

    • Author(s)
      Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Shimura M, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      Keystone symposia -Mitochondrial biology (Z1)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of novel disease-causing genes associated with mitochondrial dynamics in mitochondrial disorders2018

    • Author(s)
      Kishita Y, Kohda M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Shimura M, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      1st International Mitochondria Meeting for Young Scientists
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genetic background of Japanese patients with mitochondrial disorders2017

    • Author(s)
      Kishita Y, Kohda M, Mizuno Y, Imai A, Nakaya A, Hirata T, Yatsuka Y, Borna NN, Harashima H, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      EUROMIT2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ミトコンドリア病における他の疾患を引き起こす遺伝子変異の発見2017

    • Author(s)
      木下 善仁,神田 将和,八塚由紀子,平田 智子,水野 洋介,今井-岡﨑 敦子,原嶋 宏子,村山  圭,大竹  明,岡﨑 康司
    • Organizer
      第59回日本先天代謝異常学会総会/第15回 アジア先天代謝異常症シンポジウム
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Identification of mutations in non-mitochondrial disease genes in mitochondrial diseases2017

    • Author(s)
      Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Imai-Okazaki A, Harashima H, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      第15回RCGMフロンティアシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] Mitochondrial DNA depletion syndrome caused by homozygous mutation in MIC132016

    • Author(s)
      Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Yamazaki T, Shimura M, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      第14回RCGMフロンティア国際シンポジウム
    • Place of Presentation
      埼玉医科大学創立30周年記念講堂(埼玉県日高市)
    • Year and Date
      2016-11-11
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mitochondrial DNA depletion syndrome caused by homozygous mutation in MIC132016

    • Author(s)
      Kishita Y, Kohda M, Akita M, Mizuno Y, Yatsuka Y, Hirata T, Harashima H, Yamazaki T, Shimura M, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      The 13th Conference of Asian Society for Mitochondrial Research and Medicine [ASMRM]
    • Place of Presentation
      TKPガーデンシティ品川(東京都港区)
    • Year and Date
      2016-10-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Comprehensive genomic analysis identified mutations in nuclear-encoded mitochondria-related gene impairing mitochondrial fission and fusion balance2016

    • Author(s)
      Kishita Y, Suzuki S, Tokuzawa Y, Nyuzuki H, Kohda M, Murayama K, Ohtake A, Okazaki Y
    • Organizer
      Keystone Symposia -Mitochondrial Dynamics (D2)
    • Place of Presentation
      Sheraton Steamboat Resort (Steamboat Springs, Colorado,USA)
    • Year and Date
      2016-04-03
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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