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Richner-Hanhart症候群の高チロシン血症に伴う掌蹠過角化の発症機構

Research Project

Project/Area Number 17K10225
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Dermatology
Research InstitutionHirosaki University

Principal Investigator

赤坂 英二郎  弘前大学, 医学部附属病院, 助教 (30436034)

Co-Investigator(Kenkyū-buntansha) 澤村 大輔  弘前大学, 医学研究科, 教授 (60196334)
Project Period (FY) 2017-04-01 – 2018-03-31
Project Status Discontinued (Fiscal Year 2017)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords掌蹠角化症 / 高チロシン血症 / Richner-Hanhart症候群 / チロシンアミノトランスフェラーゼ / TAT
Outline of Annual Research Achievements

本研究の目的は,血清チロシン濃度が表皮細胞の角化にどのような影響を及ぼすかを明らかにすることである.Richner-Hanhart症候群(RHS)は,TAT遺伝子の変異によりチロシンアミノ変換酵素の活性が低下することで,高チロシン血症を呈し掌蹠に過角化を呈する稀な遺伝性皮膚疾患である.高チロシン血症により掌蹠のみに過角化が起こるメカニズムは,現在のところ解明されてない.
我々はまず,RHS患者皮膚を詳細に検討した.掌蹠荷重部位に淡黄色調の過角化がみられ,病理組織では過角化,表皮肥厚,顆粒層肥厚,多核角化細胞を認めた.血清チロシン値は正常上限の約14倍と高値であったが,低チロシン・フェニルアラニン食餌療法を行い,チロシン値が低下すると,速やかに掌蹠の過角化は改善した.
次にTAT遺伝子変異検索を行った.TAT遺伝子にc.449delTの送気停止コドンとなる欠失変異と,c.408+1G>Aのスプライシング異常が複合へテロ接合性にみられた.どのようなスプライシング異常が生じるか確認するため,TAT mRNAを用いたRT-PCRを行うこととした.肝細胞,末梢血白血球,角化細胞,線維芽細胞,健常人毛根組織を用いてRT-PCRを行ったところ,角化細胞以外でTAT mRNA発現を認めた.最も低侵襲にTAT mRNAを得るため,患者末梢血白血球および患者毛根組織からmRNAを抽出しRT-PCRを行ったが,いずれもTAT mRNA発現は確認できなかった.これは,スプライシング異常が早期停止コドンを誘導する変異であり,ナンセンス依存性RNA分解(NMD)を受けたためと考えられた.しかしながら,NMD阻害剤を用いれば,患者末梢血白血球や毛根を用いた非侵襲的なmRNAレベルでのTAT変異検索が可能になる可能性が示唆された.

Report

(1 results)
  • 2017 Annual Research Report
  • Research Products

    (6 results)

All 2017

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Journal Article] Multiple milia as an isolated skin manifestation of dominant dystrophic epidermolysis bullosa: Evidence of phenotypic variability.2017

    • Author(s)
      Akasaka E, Nakano H, Takagi Y, Toyomaki Y, Sawamura D
    • Journal Title

      Pediatr Dermatol

      Volume: 34 Issue: 2

    • DOI

      10.1111/pde.13047

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The first case of multiple pilomatricomas caused by somatic mutations of CTNNB1 without any associated disorder.2017

    • Author(s)
      Akasaka E, Nakano H, Fukui T, Korekawa A, Aizu T, Sawamura D
    • Journal Title

      J Dermatol Sci

      Volume: 88 Issue: 2 Pages: 259-260

    • DOI

      10.1016/j.jdermsci.2017.06.011

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Elevated serum IgE level, but not TARC and LDH, may reflect the impairment of stratum corneum barrier function in healthy individuals; Results of cross-sectional study of 1141 Japanese healthy individuals2017

    • Author(s)
      Eijiro Akasaka, Kenji Hara, Mika Takahashi, Tomohisa Fukui, Ayumi Korekawa, Hajime Nakano, Ippei Takahashi, Shigeyuki Nakaji, Daisuke Sawamura
    • Organizer
      76th Annual Meeting of Society for Investigative Dermatology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Peripheral blood mononuclear cells may contain a small amount of mesenchymal stem cells which express type VII collagen.2017

    • Author(s)
      Eijiro Akasaka, Hajime Nakano, Daisuke Sawamura
    • Organizer
      17th World Dermatology Congress
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mutational analysis of Porphyria in Japan2017

    • Author(s)
      Eijiro Akasaka, Hajime Nakano, Daisuke Sawamura
    • Organizer
      8th Asia and Oceania Conference on Photobiology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Serum levels of thymus and activation-regulated chemokine can be a useful marker for pruritus of healthy individuals2017

    • Author(s)
      Eijiro Akasaka, Kenji Hara, Mika Takahashi, Tomohisa Fukui, Ayumi Korekawa, Hajime Nakano, Ippei Takahashi, Shigeyuki Nakaji, Daisuke Sawamura
    • Organizer
      42nd Annual Meeting of the Japanese Society of Investigative Dermatology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2018-12-17  

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