Loss-of-function variants in DUSP1 encoding dual specificity phosphatase 1 cause palmoplantar keratoderma

Abstract Background Dual specificity phosphatase 1 (DUSP1) has recently been shown to regulate keratinocytes (KCs) proliferation through ERK signaling. Aims We aimed at delineating the genetic basis underlying inherited palmoplantar keratoderma (PPK) in two families. Material and Methods We used whole exome and direct sequencing, RT-qPCR, protein modeling, immunofluorescence confocal microscopy, immunoblotting, three-dimensional skin equivalents and the dispase dissociation assay. Results Whole exome sequencing revealed two variants in DUSP1 (c.809T>G, p.Leu270Arg and c.251T>A, p.Val84Glu) encoding DUSP1, in four individuals with PPK belonging to two unrelated families affected by a semi-dominant form of PPK. Bioinformatics and protein modeling predicted the variants to be pathogenic. Primary human KCs transfected with constructs expressing the PPK-causing pathogenic variants in DUSP1 showed decreased DUSP1 expression and concomitant increased expression of p-ERK1/2 as well as reduced DSG1 expression. Accordingly, primary human KCs downregulated for DUSP1 displayed disrupted cell-to-cell adhesion, increased p-ERK1/2 and reduced DSG1 expression. Three-dimensional organotypic skin equivalents downregulated for DUSP1 demonstrated reduced DSG1 expression and increased epidermal thickness, reminiscent of the human phenotype. ERK1/2 inhibition rescued this abnormal phenotype. Conclusions The present study attributes to DUSP1 a hitherto unrecognized role in epidermal differentiation and expand the spectrum of genetic defects known to cause inherited PPK.