838 Pathogenic frameshift peptides form unique multi-functional droplets in ichthyosis with confetti

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