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Identification of novel pathogenic variants caused by defects of interstrand DNA crosslink repair

Research Project

Project/Area Number 16K21084
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Genome biology
Risk sciences of radiation and chemicals
Research InstitutionNagoya University

Principal Investigator

OKA Yasuyoshi  名古屋大学, 環境医学研究所, 特任助教 (60762383)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsDNA損傷応答 / DNA修復 / 遺伝性疾患 / ゲノム不安定性 / 疾患モデル動物 / プロテオーム解析 / 造血幹細胞 / 小頭症
Outline of Final Research Achievements

The goal in this study is to identify novel pathogenic variants caused by the loss of genome stability from patients with microcephaly. Whole exome sequencing identified possible pathogenic variants in two different aldehyde metabolism-related genes from Japanese patients with short stature, microcephaly and hematological abnormality. To understand the molecular mechanisms by which the digenic variants cause microcephaly and hematological abnormality, we performed cellular experiments using cells derived from patients, knockout cell lines using CRISPR/Cas9-mediated genome editing technology, and umbilical cord blood CD34+ cells. These experiments showed two different aldehyde metabolism-related genes contribute to genome maintenance and hematopoietic homeostasis synergistically because simultaneous loss of function of two aldehyde metabolism-related genes leads to hypersensitivity to genotoxic stress or low differentiation ability of hematopoietic stem and progenitor cells in vitro.

Academic Significance and Societal Importance of the Research Achievements

ゲノム安定化維持機構に異常を持った劣性遺伝性疾患の臨床像として小頭症を呈する患者群に着目し、ICL修復との関連性から新規の原因遺伝子変異を探すというアプローチは前例がなく、斬新である。本研究では、ゲノムの不安定化により発症した新規の劣性遺伝性疾患の発症原因となる候補遺伝子変異を同定しており、小頭症発症の詳細な分子メカニズムの解明に繋が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

    (15 results)

All 2019 2018 2017 2016 Other

All Presentation (13 results) (of which Int'l Joint Research: 2 results) Remarks (2 results)

  • [Presentation] マルチオミクス解析により同定した重症アイカルディ・ゴーティエ症候群の分子病態解析.2019

    • Author(s)
      岡 泰由, 荻 朋男.
    • Organizer
      第41回日本小児遺伝学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Identification of pathogenic mutations in patients with rare diseases using multiomics approaches.2018

    • Author(s)
      Oka Y, Ogi T.
    • Organizer
      Japanese Proteomics Society 2018 Conference (JPrOS 2018), 9th Asia-Oceania Human Proteome Organization (AOHUPO), and 66th Annual Conference on Mass Spectrometry
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Molecular pathogenesis underlying Cockayne syndrome and UV-sensitive syndrome.2017

    • Author(s)
      Jia N, Guo C, Oka Y, Nakazawa Y, M Shimada, H Miyazaki, T Ogi.
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] マルチオミクス解析による希少遺伝性疾患発症責任因子の同定.2017

    • Author(s)
      岡泰由、中沢由華、荻朋男.
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] ゲノム不安定性を示す遺伝性疾患群の疾患責任遺伝子変異の探索.2017

    • Author(s)
      中沢由華、千住千佳子、岡泰由、嶋田繭子、宮崎仁美、郭朝万、賈楠、荻朋男
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Very mild CS type-IV cases with mutations in the CSB gene.2017

    • Author(s)
      Jia N, Guo C, Oka Y, Nakazawa Y, M Shimada, H Miyazaki, T Ogi.
    • Organizer
      第24回DNA複製・組換え・修復ワークショップ
    • Related Report
      2017 Research-status Report
  • [Presentation] Identification of pathogenic mutations in patients with rare diseases using multi-omics analysis.2017

    • Author(s)
      Oka Y, Nakazawa Y, Ogi T.
    • Organizer
      日本プロテオーム学会2017年大会
    • Related Report
      2017 Research-status Report
  • [Presentation] DNA修復機構欠損性疾患の病態解明研究2017

    • Author(s)
      中沢由華、賈楠、嶋田繭子、宮崎仁美、千住千佳子、郭朝万、岡泰由、荻朋男
    • Organizer
      第2回放射線災害・医科学研究拠点カンファランス
    • Related Report
      2017 Research-status Report
  • [Presentation] トランスオミクス解析を用いた希少遺伝性疾患原因因子の新規同定法の開発2016

    • Author(s)
      岡 泰由、郭 朝万、賈 楠、唐田清伸、中沢由華、荻 朋男
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] ゲノム不安定性を示す遺伝性疾患群の病態解析と新規疾患責任遺伝子変異探索2016

    • Author(s)
      中沢由華、岡 泰由、郭 朝万、賈 楠、唐田清伸、嶋田繭子、宮﨑仁美、千住千佳子、荻 朋男
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] コケイン症候群と紫外線高感受性症候群の分子病態解析2016

    • Author(s)
      賈 楠、中沢由華、郭 朝万、唐田清伸、岡 泰由、嶋田繭子、宮﨑仁美、千住千佳子、荻 朋男
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] TC-NER因子UVSSAによるRNAポリメラーゼIIのユビキチン化に関する分子機能解析2016

    • Author(s)
      郭 朝万、中沢由華、嶋田繭子、唐田清伸、賈 楠、岡 泰由、宮﨑仁美、千住千佳子、荻 朋男
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Screening of microcephaly cases to identify pathogenic mutations in DNA repair genes2016

    • Author(s)
      Oka Y, NakazawaY, Karata K, Guo C, Lehmann AR, Ogi T
    • Organizer
      The 10th 3R Symposium
    • Place of Presentation
      松江
    • Year and Date
      2016-11-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 名古屋大学環境医学研究所HP

    • URL

      http://www.riem.nagoya-u.ac.jp/index.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 名古屋大学環境医学研究所 発生遺伝分野HP

    • URL

      http://www.riem.nagoya-u.ac.jp/4/genetics/index.html

    • Related Report
      2018 Annual Research Report

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

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