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Analysis of generation mechanisms of somatic revertant mutations and development of their control methods aiming at new cell medicine strategy

Research Project

Project/Area Number 18K19540
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionNagoya University

Principal Investigator

AKIYAMA Masashi  名古屋大学, 医学系研究科, 教授 (60222551)

Project Period (FY) 2018-06-29 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Keywords遺伝子 / 体細胞復帰変異 / モザイク / 魚鱗癬 / 表皮 / 角化 / 復帰変異 / 魚燐癬
Outline of Final Research Achievements

In this study, we focused on ichthyosis with confetti (IWC), a subtype of epidermolytic ichthyoses caused by heterozygous KRT1 or KRT10 mutations. In this disease, somatic revertant mosaicism occurs at an abnormally high frequency. Healthy tissue made by somatic revertant mosaicism is ideal as a cell medicine because it consists of the patient's own cells and does not have immunogenicity. In IWC, mutations are concentrated in specific regions of the causative genes KRT1 and KRT10, but the reason why the somatic revertant mosaicism occurs frequently is unknown. Since the genome size of KRT1 is as small as about 4.5 kb and it is extremely suitable for genetic manipulation. In this study, we tried to create a model cell line and a model animal system of IWC by introducing heterozygous gene mutations into the KRT1 gene by CRISPR-Cas9, and aimed to elucidate the molecular mechanism of the somatic revertant mosaicism using those systems.

Academic Significance and Societal Importance of the Research Achievements

本研究ではichthyosis with confetti(IWC)のモデル実験系の作成を目指し、体細胞復帰突然変異によるモザイク現象を人為的に発生させる技術の創出を目標とした。IWCにおいて体細胞復帰突然変異によるモザイク現象が多発する事は、mitotic recombinationの発生頻度を調節する未知のメカニズムが細胞内に存在する事を示している。その意義は不明であるが、病的遺伝子存在下での個体の健全性を担保している可能性が示唆される。mitotic recombinationの発生頻度を調節する未知のメカニズムが解明されれば、細胞生物学的に新しい概念が提示されることになる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018 Other

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

  • [Journal Article] Recurrent KRT10 variant in ichthyosis with confetti.2020

    • Author(s)
      Takeichi T, Suga Y, Mizuno T, Okuno Y, Ichikawa D, Kono M, Lee JYW, McGrath JA, Akiyama M.
    • Journal Title

      Acta Dermato-Venereol

      Volume: 100 Issue: 14 Pages: adv00209-adv00209

    • DOI

      10.2340/00015555-3570

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mild epidermolytic ichthyosis with palmoplantar keratoderma due to the KRT1 mutation p.lle479Thr.2020

    • Author(s)
      Murase Y, Tanahashi K, Takeichi T, Sugiura K, Aiyama A, Nishida K, Mitsuma T, Akiyama M.
    • Journal Title

      J Dermatol

      Volume: 47 Issue: 9

    • DOI

      10.1111/1346-8138.15476

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma2019

    • Author(s)
      Suzuki Shotaro、Nomura Toshifumi、Miyauchi Toshinari、Takeda Masae、Fujita Yasuyuki、Nishie Wataru、Akiyama Masashi、Ishida-Yamamoto Akemi、Shimizu Hiroshi
    • Journal Title

      Life Science Alliance

      Volume: 2 Issue: 1 Pages: e201800284-e201800284

    • DOI

      10.26508/lsa.201800284

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Studies on differentiation-dependent expression and activity of distinct transglutaminases by specific substrate peptides using three dimensional reconstituted epidermis.2019

    • Author(s)
      Tanabe Y., Yamane M, Kato M., Teshima H., Kuribayashi M., Tatsukawa H., Takama H., Akiyama M.,  Hitomi K.
    • Journal Title

      FEBS J.

      Volume: in press Issue: 13 Pages: 2536-2548

    • DOI

      10.1111/febs.14832

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes.2018

    • Author(s)
      Nomura T, Suzuki S, Miyauchi T, Takeda M, Shinkuma S, Fujita Y, Nishie W, Akiyama M, Shimizu H
    • Journal Title

      JCI Insight

      Volume: 3 Issue: 6

    • DOI

      10.1172/jci.insight.97595

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 角化症を科学する2020

    • Author(s)
      秋山真志
    • Organizer
      第71回日本皮膚科学会中部支部学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 皮膚科医である私の表皮細胞生物学への取り組み2019

    • Author(s)
      秋山真志
    • Organizer
      第118回日本皮膚科学会総会(国内学会)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 表皮融解性母斑を持つ父と表皮融解性魚鱗癬の子の親子例:次世代での表皮融解性魚鱗癬発症リスク予測2018

    • Author(s)
      秋山真志
    • Organizer
      第466回日本皮膚科学会大阪地方会
    • Related Report
      2018 Research-status Report
  • [Remarks] 名古屋大学大学院医学系研究科皮膚科学分野のホームページ

    • URL

      https://www.med.nagoya-u.ac.jp/derma/

    • Related Report
      2020 Annual Research Report 2019 Research-status Report 2018 Research-status Report

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Published: 2018-07-25   Modified: 2022-01-27  

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