Reframing nonsense variants in genodermatoses through personalized molecular rescue

Nonsense variants offer a promising therapeutic target in genodermatoses because premature translation termination can potentially be bypassed. A premature termination codon (PTC) can produce a truncated protein and trigger nonsense-mediated mRNA decay (NMD), reducing the transcript available for protein synthesis. Even partial restoration may be biologically meaningful. In COL17A1-related junctional epidermolysis bullosa (JEB), genotype-phenotype studies have shown that C17 expression at only approximately 12%–14% of normal levels can ameliorate the disease phenotype.