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

Abstract

Dual specificity phosphatase 1 (DUSP1) has recently been shown to regulate keratinocyte (KC) proliferation through extracellular regulated kinase (ERK) signalling. To delineate the genetic basis underlying inherited palmoplantar keratoderma (PPK) in two families. We used whole-exome and direct sequencing, quantitative real-time polymerase chain reaction, protein modelling, immunofluorescence confocal microscopy, immunoblotting, three-dimensional skin equivalents and the dispase-based KC dissociation assay. 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 semidominant form of PPK. Bioinformatics and protein modelling 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 phosphorylated (p-)ERK1/2, as well as reduced desmoglein 1 (DSG1) expression. Accordingly, primary human KCs downregulated for DUSP1 displayed disrupted cell-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. This study attributes to DUSP1 a hitherto unrecognized role in epidermal differentiation and expands the spectrum of genetic defects known to cause inherited PPK.