861 CTSZ pathogenic variants affect EGFR expression and cause autosomal dominant palmoplantar keratoderma

Abnormal function of the epidermal growth factor receptor (EGFR) has been recently shown to underlie various disorders cornification. Here we aimed at delineating genetic basis a novel dominant form palmoplantar keratoderma (PPK). Whole exome sequencing revealed heterozygous variants in CTSZ encoding cathepsin Z 4 affected individuals belonging 3 unrelated families. Bioinformatics and protein modeling predicted be pathogenic. Previous studies had suggested that EGFR expression may subject regulation. Immunostaining reduced upper layers concomitant increased patients harboring variants. Accordingly, human keratinocytes (KCs) transfected with constructs expressing these displayed enzymatic activity as well expression, demonstrated by immunoblotting immunostaining. In line role played regulation KC proliferation, KCs PPK-causing showed abnormally proliferation which could rescued erlotinib, an inhibitor. Further supporting for homeostasis, downregulation resulted compared control cells, suggestive loss effect pathogenic Finally, 3D organotypic skin equivalents grown from CTSZ-downregulated cells thickness seen patient skin. Erlotinib normalized CTSZ-down-regulated equivalents. Taken collectively, observations attribute hitherto unrecognized normal differentiation.