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2017 年度 実施状況報告書

Establishment of an integrated database of DNA repair deficiency disorders

研究課題

研究課題/領域番号 17K17806
研究機関名古屋大学

研究代表者

賈 楠  名古屋大学, 環境医学研究所, 特任助教 (90754060)

研究期間 (年度) 2017-04-01 – 2019-03-31
キーワードDDR-deficient disorders / Cockyane Syndrome / UV-sensitive syndrome
研究実績の概要

DNA damage response (DDR) system is important for maintenance of genome integrity; defects in DDR system can result in deleterious consequences, including cancer and genetic disorders. For more precise diagnosis and better understanding of the mechanisms underlying DDR-deficient disorders, we worked on collecting DDR deficiency patient samples from all over the world, followed by establishment of cell bank, as well as large scale screening of DNA repair activities, gene diagnosis and identification of founder mutations. Till now over 1000 samples have been collected and stocked in proper way. We, together with collaborators from Italy, France and UK, finished diagnosis of 124 patients with Cockyane Syndrome (CS), and identified 71 novel pathogenic mutations in the CSA and CSB genes. Our results provide insight into previously unreported genotype-phenotype relationships and their relevance for clinical diagnosis.
We also identified several mild cases with R77* mutations in the CSB gene (CS-IV patients). In our research we found distinct cellular responses between CS-IV patients and other severe CS patients after UV damage, and this difference may be related to diverse severity of CS clinical phenotype.

現在までの達成度 (区分)
現在までの達成度 (区分)

2: おおむね順調に進展している

理由

1.We have collected over 1000 samples and have made the cell stock as well as performed gene diagnosis of most of samples.
2.For research on functional analysis of CS and UV-sensitive syndrome (UVSS) patients, we collected samples from with different clinical spectrum including CS-I, CS-II, CS-III and CS-IV, and found the break point to explain diverse CS phenotype.

今後の研究の推進方策

1.We will keep on collecting samples, performing gene diagnosis and functional analysis, to identify novel genes and mutations, as well as to search genotype-phenotype correlations underlying DDR deficiency disorders.
2.We are also working on investigate the genotype-phenotype correlations in CS, and going to perform the following experiments: i, identify the common alternative transcripts in all CS-IV patients as they carry the same mutation; ii, investigate whether the putative alternative transcripts are related to the unique cellular response in CS-IV patients after UV damage; iii, generate mouse model for analysis of genotype-phenotype correlation and for drug development.

次年度使用額が生じた理由

In this year, most of the collected samples we analyzed are CS patients with mutations in the CSA and CSB genes, which we could perform precise gene diagnosis with standard Sanger Sequence instead of costly Next Generation Sequence (NGS).
The saved budget will be used in: (1) diagnosis of cases with DNA repair defects that unknown genes are involved with NGS and Mass spectrum (MS); (ii) consumables of functional analysis, including RNA-sequence and mice experiments, and et al.

  • 研究成果

    (5件)

すべて 2018 2017

すべて 雑誌論文 (1件) (うち国際共著 1件、 査読あり 1件、 オープンアクセス 1件) 学会発表 (4件)

  • [雑誌論文] Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome2018

    • 著者名/発表者名
      Calmels Nadege、Botta Elena、Jia Nan、Fawcett Heather、Nardo Tiziana、Nakazawa Yuka、Lanzafame Manuela、Moriwaki Shinichi、Sugita Katsuo、Kubota Masaya、Obringer Cathy、Spitz Marie-Aude、Stefanini Miria、Laugel Vincent、Orioli Donata、Ogi Tomoo、Lehmann Alan Robert
    • 雑誌名

      Journal of Medical Genetics

      巻: 55 ページ: 329~343

    • DOI

      10.1136/jmedgenet-2017-104877

    • 査読あり / オープンアクセス / 国際共著
  • [学会発表] Very mild CS type-IV cases with mutations in the CSB gene2017

    • 著者名/発表者名
      Nan Jia, Chaowan Guo, Yasuyoshi Oka, Yuka Nakazawa, Mayuko Shimada, Hitomi Miyazaki, Tomoo Ogi
    • 学会等名
      第24回DNA複製・組換え・修復ワークショップ
  • [学会発表] Molecular pathogenesis underlying Cockayne syndrome and UV-sensitive syndrome2017

    • 著者名/発表者名
      Nan Jia, Chaowan Guo, Yasuyoshi Oka, Yuka Nakazawa, Mayuko Shimada, Hitomi Miyazaki, Tomoo Ogi
    • 学会等名
      第40回日本分子生物学会年会
  • [学会発表] 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

    • 著者名/発表者名
      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
    • 学会等名
      2017年度生命科学系学会合同年次大会
  • [学会発表] DNA修復機構欠損性疾患の病態解明研究2017

    • 著者名/発表者名
      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
    • 学会等名
      第2回放射線災害・医科学研究拠点カンファランス

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公開日: 2018-12-17  

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