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 keratinocyte (KC) proliferation through extracellular regulated kinase (ERK) signalling.

Objectives: To delineate the genetic basis underlying inherited palmoplantar keratoderma (PPK) in two families.

Methods: 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.

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 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.

Conclusions: This study attributes to DUSP1 a hitherto unrecognized role in epidermal differentiation and expands the spectrum of genetic defects known to cause inherited PPK.