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.