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- W4366171306 abstract "Ichthyosis with confetti (IWC) is a rare autosomal dominant disorder caused by frameshift mutations in KRT10 or KRT1 gene. IWC is characterized by widespread ichthyosiform erythroderma and, more notably, concomitant revertant skin patches, also known as natural gene therapy (Choate et al., 2010; Suzuki et al., 2016; Nomura et al., 2018). Although homologous recombination underlies revertant mosaicism in IWC, the molecular mechanism how mutant KRT10 or KRT1 induces genetic reversion remains unknown. KRT10 is a cytoskeletal and microfibrillar protein that gives physical strength to suprabasal keratinocytes, leading to the formation of epidermal barrier. Consistently, nonsense or missense mutations in KRT10 gene cause epidermolytic ichthyosis (EI) that shows the strong skin fragility such as erosions and bullae due to its protein deficiency or dysfunction. However, frameshift mutations at the tail domain in KRT10 gene show the no/mild skin fragility, but cause revertant mosaicism. Therefore, IWC is supposed to have different pathology from EI. In this study, we investigated the molecular principles underlying the toxicity of the IWC-causing frameshift peptides. Given that frameshift peptides are composed of repetitive arginine-rich regions with low sequence complexity, we suspected that change in physical properties of KRT10 protein due to C-terminal frameshift mutations triggers distinct pathogenic functions. We found that IWC-causing frameshift peptides have intrinsically disordered regions and form membraneless organelle through liquid-liquid phase separation in the nucleolus. Our genetic and biological experiments show that specific physical interaction between frameshift peptides and various biomolecules provides the unique and toxic functions by using the droplet as a reaction platform, that lead to protein repression and aggregation, which is not observed in EI-causing mutant KRT10." @default.
- W4366171306 created "2023-04-19" @default.
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- W4366171306 date "2023-05-01" @default.
- W4366171306 modified "2023-09-28" @default.
- W4366171306 title "838 Pathogenic frameshift peptides form unique multi-functional droplets in ichthyosis with confetti" @default.
- W4366171306 doi "https://doi.org/10.1016/j.jid.2023.03.848" @default.
- W4366171306 hasPublicationYear "2023" @default.
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