Transcriptomic and proteomic analysis of MVK variant sites in two subtypes of porokeratosis.

Porokeratosis (PK) encompasses genetically heterogeneous keratinization disorders, with disseminated superficial actinic porokeratosis (DSAP) and porokeratosis ptychotropica (PPt) as distinct subtypes. Although MVK is a known causative gene, how different variants drive distinct phenotypes remains unclear. Through whole-exome sequencing of two DSAP patients, we identified an MVK variant (c.439G > A, p.Ala147Thr) cataloged as likely pathogenic in ClinVar yet uncharacterized functionally in DSAP keratinocytes. A previously reported PPt-associated variant (c.64G > A) was included for comparison. We established HaCaT cells stably overexpressing each mutant via lentiviral transduction and validated expression by qPCR and Western blot. Integrated transcriptomic and proteomic analyses identified differentially expressed genes (DEGs) and proteins (DEPs) across MVK439 versus control, MVK64 versus control, and MVK439 versus MVK64 groups, followed by GO and KEGG enrichment. Transcriptomic profiling revealed 231, 1,849, and 2,329 DEGs in the respective comparisons. Proteomic screening identified 2,673 DEPs, with 42 shared across all groups, 77 specifically associated with c.439G > A, and 832 linked to c.64G > A. Integrated analysis suggested IL12A and pIgR as potential contributors to c.439G > A-driven DSAP, while CXCL11, CXCL9, and TNFRSF12A may mediate c.64G > A-induced PPt. These findings offer new insights into MVK function and PK pathogenesis, warranting validation in larger cohorts.