A steadily growing number of hereditary palmoplantar keratodermas (PPKs) have been found to result from defective function of epidermal adhesion proteins such as desmoglein 1 (DSG1), a critical component of desmosomes which has been implicated in the pathogenesis of striate, diffuse and focal PPKs. Here we aimed at delineating the genetic basis of a novel dominant form of PPK. We studied three patients from two families diagnosed with PPK. Whole exome sequencing revealed causative pathogenic heterozygous variants in KLF4 gene in the three affected individuals. Immunofluorescence staining revealed reduced epidermal desmoglein 1 (DSG1) expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or down-regulated for KLF4, displayed reduced DSG1 expression, which has previously been found to be associated with PPK. A ChIP assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to trans-activate the DSG1 promoter was significantly decreased. In Conclusion, Loss-of-function variants in KLF4 cause a novel form of dominant PPK and demonstrate its importance in the regulation of epidermal differentiation.

ESDR259 - KLF4 variants: a novel cause of palmoplantar keratoderma

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.