Elucidation of the Molecular Basis of Congenital Ichthyosis Onset and Natural gene therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16256
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: University of Tsukuba
• Principal Investigator: SUGIYAMA Takato 筑波大学, 医学医療系, 特別研究員(PD) (70930329)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: ケラチン / 相分離 / 天然変性タンパク質

Outline of Final Research Achievements

Congenital ichthyosis caused by mutations in the keratin 10 gene includes epidermolytic ichthyosis and Ichthyosis with confetti (IWC), which display significantly different clinical presentations. Additionally, IWC is an extremely rare hereditary disease that causes natural gene therapy, but it remains unclear why different types of diseases develop from mutations in the same gene. In this study, we revealed that the tail region of wild-type keratin 10 is an intrinsically disordered region that induces liquid-liquid phase separation, whereas IWC mutant keratin 10 forms different structures. It is suggested that the IWC mutation significantly alters the physical properties and flexibility of the keratin tail region, leading to the development of IWC.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

遺伝性疾患には根治的治療法が存在しない、というのが現代の常識である。一方で、IWCという極めて珍しいタイプの魚鱗癬では、revertant mosaicismという現象により、遺伝子変異が自然に治癒することが知られている。このように、「ヒトが元来から備える能力によって、ゲノムを修正し、細胞が遺伝性疾患を治療する」という現象の分子基盤を理解することは、将来的な遺伝性疾患の新たな治療法開発に向けた基盤的研究になりうる。