La proteómica revela alteración de la biosíntesis de lípidos e hiperfosforilación de queratina en la paquioniquia...

Pachyonychia congenita (PC) is a rare and painful skin disorder caused by dominant pathogenic variants in keratin genes (KRT6A/KRT6B/KRT6C/KRT16/KRT17), with no effective treatment. We developed a scalable, in-depth and miniaturized MS-based proteomics and phospho-proteomics analysis of full-thickness skin biopsies applied to 10 PC patients to elucidate pathogenic mechanisms and pinpoint therapeutic targets. We quantified 7200 Protein Groups (PGs) on average from 2mm snap-frozen skin samples, the most in-depth proteome coverage reported to date from a single-shot MS analysis. Among the identified PGs, ∼1400 proteins were differentially abundant in lesional vs. non-lesional samples. Enrichment analysis points towards impaired mitochondrial function, hyper-keratinization, enhanced immune response and a significant increase in cholesterol biosynthesis. Phosphoproteomics revealed hyper-phosphorylation of specific sites in PC-related keratins, confirmed the hyper-activation of EGFR and downstream kinases, including PKC and Src, and disclosed p38 MAPK activation. All of these kinases have been reported to phosphorylate keratins. Our study expands upon current understanding of the consequences of EGFR pathway activation, including increased cholesterol biosynthesis, thereby renewing interest in the use of statins for PC. Above all, it provides a solid foundation for the continued exploration of EGFR inhibitors and offers therapeutic avenues, particularly those using multikinase inhibitors.