Therapeutic p63 isoform switching rescues epidermal defects in AEC syndrome.

Abstract

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a debilitating genodermatosis marked by skin erosions and caused by dominant mutations in TP63, a crucial transcriptional regulator of epidermal gene expression. These mutations localize to a carboxy-terminal domain unique to p63α, where they disrupt folding, promote aggregation, and impair transcriptional activity. Here, we uncover an isoform-specific therapeutic strategy to bypass this pathogenic mechanism. Using a conditional mouse model with targeted deletion of Trp63 exon 13, we induced isoform switching from p63α to p63β. While p63α was indispensable for limb and palate development, p63β fully supported epidermal stratification, adult skin homeostasis, and wound healing. Despite the isoform shift, p63 retained its chromatin-binding landscape and sustained transcriptional programs essential for epidermal identity and maintenance. Extending these findings to human cells, we used CRISPR-Cas9 to delete TP63 exon 13 in primary keratinocytes, inducing p63β without affecting proliferation or global transcription. Switching to p63β in AEC patient-derived keratinocytes reversed hallmark molecular defects, resolving aggregation, reestablishing transcriptional identity, and restoring mechanical resilience. Our results establish isoform switching as a viable, mutation-agnostic therapeutic strategy for AEC syndrome.