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Establishment of novel non-invasive diagnostic methods for mitochondrial cardiomyopathy

Research Project

Project/Area Number 20K08497
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionJuntendo University

Principal Investigator

OKAZAKI ATSUKO  順天堂大学, 大学院医学研究科, 准教授 (70761691)

Co-Investigator(Kenkyū-buntansha) 山崎 悟  国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70348796)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywordsミトコンドリア病 / 心筋症 / ミトコンドリア心筋症 / ヘテロプラスミー / ヘテロプラスミー率 / ミトコンドリアDNA / 遺伝性心筋症 / 非侵襲的診断法 / digital PCR / 変異ミトコンドリアDNA率(ヘテロプラスミー率)
Outline of Research at the Start

ミトコンドリア心筋症の診断が困難な一因として、変異ミトコンドリアDNAは主に心筋に存在するため診断には心筋組織が必要であることが挙げられる。申請者らはミトコンドリア心筋症例の各組織中で、尿検体が心筋の変異ミトコンドリアDNA率と良く相関する事実を発見した。申請者らは891例の自験データに基づく変異ミトコンドリアDNA定量化システムを開発し、132例のミトコンドリア病患者での検証に成功した。本研究では新規開発した変異ミトコンドリアDNA定量化システムを発展させて心筋症に最適化した変異定量化システムを開発し、非侵襲的に入手可能な尿検体を用いたミトコンドリア心筋症の新規診断法の確立を目的とする。

Outline of Final Research Achievements

We successfully established novel non-invasive diagnostic methods for mitochondrial cardiomyopathy. Firstly we completed dataset where we compared heteroplasmy in urine with that in heart tissue in several mitochondrial cardiomyopathy patients. Secondly, by using those dataset, we developed novel diagnostic systems for quantifying mitochondrial DNA heteroplasmy rate in urine using droplet digital PCR. In addition, we published our evidence on relation between genetic background including mitochondrial DNA heteroplasmy rate and prognosis in mitochondrial cardiomyopathy patients.

Academic Significance and Societal Importance of the Research Achievements

確立した診断法が存在しないミトコンドリア心筋症の診断率の向上は長年の課題であった。申請者らの開発した変異ミトコンドリアDNA定量化システムは、非侵襲的に入手可能な尿検体を用いてミトコンドリア心筋症の診断が可能となる手法であり、心筋生検という侵襲を必要としないという利点を有する。さらに現在定量化手法の存在しないミトコンドリアDNA欠失変異に対しても、欠失部位によらず定量化が可能である。本システムは臨床現場で活用できるミトコンドリア心筋症の診断ツールとしての有用性を持つ。さらに変異ミトコンドリアDNA率と心筋症重症度、予後との相関はミトコンドリア心筋症に対する心臓移植適応のエビデンス構築に役立つ。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (24 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (2 results) Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 3 results) Presentation (8 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Book (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Rockefeller University(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Rockefeller University(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease2022

    • Author(s)
      Imai-Okazaki A, Nitta KR, Yatsuka Y, Sugiura A, Arao M, Shimura M, Ebihara T, Onuki T, Ichimoto K, Ohtake A, Murayama K, Okazaki Y.
    • Journal Title

      J Inherit Metab Dis.

      Volume: 45 Issue: 6 Pages: 1143-1150

    • DOI

      10.1002/jimd.12547

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Machine learning approaches to explore digenic inheritance.2022

    • Author(s)
      Okazaki A, Ott J.
    • Journal Title

      Trends Genet.

      Volume: 38 Pages: 1013-1018

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of Leigh syndrome with a high probability of cardiac manifestations in infantile-onset patients with m.14453G>A2022

    • Author(s)
      Masaru Shimura, Takanori Onuki, Yohei Sugiyama, Tetsuro Matsuhashi, Tomohiro Ebihara, Takuya Fushimi, Makiko Tajika, Keiko Ichimoto, Ayako Matsunaga, Tomoko Tsuruoka, Kazuhiro R Nitta, Atsuko Imai-Okazaki, Yukiko Yatsuka, Yoshihito Kishita, Akira Ohtake, Yasushi Okazaki, Kei Murayama
    • Journal Title

      Mitochondrion.

      Volume: 63 Pages: 1-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitochondrial DNA depletion syndrome with a mutation in SLC25A4 developing epileptic encephalopathy: A case report2022

    • Author(s)
      Kashiki Tomoko、Kido Jun、Momosaki Ken、Kusunoki Shouichirou、Ozasa Shiro、Nomura Keiko、Imai-Okazaki Atsuko、Tsuruoka Tomoko、Murayama Kei、Koga Yasutoshi、Nakamura Kimitoshi
    • Journal Title

      Brain and Development

      Volume: 44 Issue: 1 Pages: 56-62

    • DOI

      10.1016/j.braindev.2021.08.005

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion2022

    • Author(s)
      Ebihara T, Nagatomo T, Sugiyama Y, Tsuruoka T, Osone Y, Shimura M, Tajika M, Ichimoto K, Naruke Y, Akiyama N, Lim SC, Yatsuka Y, Nitta KR, Kishita Y, Fushimi T, Okazaki A, Ohtake A, Okazaki Y, Murayama K.
    • Journal Title

      Mol Genet Metab Rep.

      Volume: 33 Pages: 100912-100912

    • DOI

      10.1016/j.ymgmr.2022.100912

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of Leigh syndrome with a high probability of cardiac manifestations in infantile-onset patients with m.14453G?>?A2022

    • Author(s)
      Shimura M, Onuki T, Sugiyama Y, Matsuhashi T, Ebihara T, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, Tsuruoka T, Nitta KR, Imai-Okazaki A, Yatsuka Y, Kishita Y, Ohtake A, Okazaki Y, Murayama K.
    • Journal Title

      Mitochondrion

      Volume: 63 Pages: 1-8

    • DOI

      10.1016/j.mito.2021.12.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neonatal-onset mitochondrial disease: clinical features, molecular diagnosis and prognosis2021

    • Author(s)
      Ebihara T, Nagatomo T, Sugiyama Y, Tsuruoka T, Osone Y, Shimura M, Tajika M, Matsuhashi T, Ichimoto K, Matsunaga A, Akiyama N, Ogawa-Tominaga M, Yatsuka Y, Nitta KR, Kishita Y, Fushimi T, Imai-Okazaki A, Ohtake A, Okazaki Y, Murayama K.
    • Journal Title

      Archives of Disease in Childhood - Fetal and Neonatal Edition

      Volume: 107 Issue: 3 Pages: 329-334

    • DOI

      10.1136/archdischild-2021-321633

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Long-term prognosis and genetic background of cardiomyopathy in 223 pediatric mitochondrial disease patients.2021

    • Author(s)
      Imai-Okazaki A, Matsunaga A, Yatsuka Y, Nitta KR, Kishita Y, Sugiura A, Sugiyama Y, Fushimi T, Shimura M, Ichimoto K, Tajika M, Tominaga M, Ebihara T, Matsuhashi T, Tsuruoka T, Kohda M, Hirata T, Harashima H, Nojiri S, Takeda A, Nakaya A, Kogaki S, Sakata Y, Ohtake A, Murayama K, Okazaki Y.
    • Journal Title

      International Journal of Cardiology

      Volume: 341 Pages: 48-55

    • DOI

      10.1016/j.ijcard.2021.06.042

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical heterogeneity in patients with m.4412G?>?A MT-TM mutation and different heteroplasmy levels2021

    • Author(s)
      Imai-Okazaki Atsuko、Yagi Nobuyasu、Nitta Kazuhiro R.、Murayama Kei、Ohtake Akira、Okazaki Yasushi
    • Journal Title

      Mitochondrion

      Volume: 59 Pages: 214-215

    • DOI

      10.1016/j.mito.2021.06.001

    • Related Report
      2021 Research-status Report
  • [Journal Article] Genotype Pattern Mining for Pairs of Interacting Variants Underlying Digenic Traits2021

    • Author(s)
      Okazaki Atsuko、Horpaopan Sukanya、Zhang Qingrun、Randesi Matthew、Ott Jurg
    • Journal Title

      Genes

      Volume: 12 Issue: 8 Pages: 1160-1160

    • DOI

      10.3390/genes12081160

    • Related Report
      2021 Research-status Report
  • [Journal Article] Population genetics: past, present, and future2020

    • Author(s)
      Okazaki Atsuko、Yamazaki Satoru、Inoue Ituro、Ott Jurg
    • Journal Title

      Human Genetics

      Volume: 140 Issue: 2 Pages: 231-240

    • DOI

      10.1007/s00439-020-02208-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Genetic Background and Clinical Presentation of Cardiomyopathy in 313 Mitochondrial Disease Patients2023

    • Author(s)
      Atsuko Okazaki, Atsuhito Takeda, Akira Ohtake, Yasushi Okazaki
    • Organizer
      第87回日本循環器学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Different mitochondrial DNA heteroplasmy distribution at the single-cell leven in MELAS2022

    • Author(s)
      Okazaki A, Yatuka Y, Arao M, Shimura M, Ebihara T, Onuki T, Ichimoto K, Ohtake A
    • Organizer
      第63回日本先天代謝異常学会学術集会/第18回アジア先天代謝異常症シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Validation and diagnosis of novel variants of mitochondrial diseases associated with the ECHS1 gene2022

    • Author(s)
      Kishita Y, Sugiura A, Onuki T, Ebihara T, Matsuhashi T, Shimura M, Fushimi T, Ichino N, Nagatakidani Y, Nishihata H, Nitta KR, Yatsuka Y, Imai-Okazaki A, Yibo W, Osaka H, Ohtake A, Murayama K, Okazaki Y.
    • Organizer
      第45回日本分子生物学会年会,
    • Related Report
      2022 Annual Research Report
  • [Presentation] Neonatal-Onset Mitochondrial Disease: Clinical Features, Molecular Diagnosis, and Prognosi2022

    • Author(s)
      Tomohiro Ebihara, Taro Nagatomo, Yohei Sugiyama, Tomoko Tsuruoka, Yoshiteru Osone, Masaru Shimura, Makiko Tajika, Tetsuro Matsuhashi, Keiko Ichimoto, Ayako Matsunaga, Nana Akiyama, Yukiko Yatsuka, Kazuhiro R. Nitta, Yoshihito Kishita, Takuya Fushimi, Atsuko Okazaki, Akira Ohtake, Yasushi Okazaki, Kei Murayama
    • Organizer
      SSIEM Annual Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Maternally inherited deafness, epilepsy and mental retardation is associated with m.12207G>A MT-TS2 mutation in a Japanese family2022

    • Author(s)
      Sayaka Ajihara, Megumi Tsuruoka, Hiroko Harashima, Torayuki Okuyama, Yukiko Yatsuka, Atuko Okazaki, Yasushi Okazaki, Kei Murayama, Yuko Akioka, Akira Ohtake
    • Organizer
      SSIEM Annual Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 小児ミトコンドリア病223症例における心筋症の遺伝的基盤および 長期予後に関する検討2021

    • Author(s)
      岡崎敦子
    • Organizer
      第30回日本小児心筋疾患学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Long-term prognosis and genetic background in 223 children with mitochondrial disease2021

    • Author(s)
      Atsuko Okazaki
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Prognosis and Genetic Background of Mitochondrial Cardiomyopathy in 223 Mitochondrial Disease Patients2020

    • Author(s)
      Atsuko Okazaki
    • Organizer
      84th Annual Scientific Meeting of the Japanese Circulation Society
    • Related Report
      2020 Research-status Report
  • [Book] 小児内科54巻4号 【特集】症例から学ぶミトコンドリア病 総論 核DNAにおける遺伝子診断の実際2022

    • Author(s)
      岡﨑 敦子、岡﨑 康司
    • Total Pages
      156
    • Publisher
      東京医学社
    • Related Report
      2022 Annual Research Report
  • [Book] 腎臓内科 第15巻 第5号 特集 腎臓とミトコンドリア ミトコンドリア病と原因遺伝子2022

    • Author(s)
      岡﨑 敦子、岡﨑 康司
    • Total Pages
      115
    • Publisher
      科学評論社
    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] 肥大型心筋症治療剤2021

    • Inventor(s)
      順天堂大学
    • Industrial Property Rights Holder
      順天堂大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-009754
    • Filing Date
      2021
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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