Defective cathepsin Z affects EGFR expression and causes autosomal dominant palmoplantar keratoderma.

BACKGROUND: The abnormal function of epidermal growth factor receptor (EGFR) has recently been shown to underlie various disorders of cornification. OBJECTIVES: To delineate the genetic basis of a novel dominant form of palmoplantar keratoderma (PPK). METHODS: Whole-exome (WES) and direct sequencing, quantitative real-time polymerase chain reaction, protein modelling, confocal immunofluorescence microscopy, immunoblotting, three-dimensional skin equivalents and an enzyme activity assay were used to delineate the genetic basis of a novel dominant form of PPK. RESULTS: WES revealed heterozygous variants (c.274T > C and c.305C > T) in CTSZ (encoding cathepsin Z) in four individuals (belonging to three unrelated families) with focal PPK. Bioinformatics and protein modelling predicted the variants to be pathogenic. Previous studies have suggested that EGFR expression may be subject to cathepsin regulation. Immunofluorescence revealed reduced cathepsin Z expression in the upper epidermal layers and concomitant increased epidermal EGFR expression in patients harbouring CTSZ variants. Accordingly, human keratinocytes transfected with constructs expressing PPK-causing variants in CTSZ displayed reduced cathepsin Z enzymatic activity, as well as increased EGFR expression. In line with the role played by EGFR in the regulation of keratinocyte proliferation, human keratinocytes transfected with the PPK-causing variants showed significantly increased proliferation that was abolished upon exposure to erlotinib, an EGFR inhibitor. Similarly, downregulation of CTSZ resulted in increased EGFR expression and increased proliferation in human keratinocytes, suggestive of a loss-of-function effect of the pathogenic variants. Finally, three-dimensional organotypic skin equivalents grown from CTSZ-downregulated cells showed increased epidermal thickness and EGFR expression as seen in patient skin; here, too, erlotinib was found to rescue the abnormal phenotype. CONCLUSIONS: Taken collectively, these observations attribute to cathepsin Z a hitherto unrecognized function in epidermal differentiation.

Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression.

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease which is to a large extent genetically determined, and results, at least in part, from the deleterious activity of autoantibodies directed against desmoglein (DSG)3, a prominent intra-epidermal adhesion molecule. Those autoantibodies lead to decreased membranal DSG3 expression in keratinocytes (KCs), thereby destabilizing cell-cell adhesion within the epidermis and leading to blister formation. We previously showed that rs17315309, a strong risk variant for PV within the promoter of the ST18 transcription factor gene, promotes epidermal ST18 up-regulation in a p53/p63-dependent manner. Accordingly, ST18 was found to be overexpressed in the skin of PV patients. Increased ST18 expression was then shown to markedly augment PV autoantibodies-mediated loss of KCs cohesion. Here, we demonstrate that ST18 overexpression significantly increases autoantibody-mediated DSG3 down-regulation in keratinocytes. In addition, DSG3 decreased expression boosts p53 function through p38 mitogen-activated protein kinase (p38MAPK) activation and dramatically augments p53-dependent ST18 promoter activity. Finally, the PV risk variant rs17315309 is associated with increased p53 expression in PV skin. Taken collectively, these observations reveal a novel self-amplifying pathomechanism involving ST18, DSG3, p38 and p53, capable of perpetuating disease activity, and therefore indicative of novel actionable molecular targets in PV.