Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma.

Background: Epidermal differentiation disorders [EDDs; ichthyosis and palmoplantar keratoderma (PPK)] are heritable skin conditions characterized by localized or generalized skin scaling and erythema.

Objectives: To identify novel genetic variants that cause PPK and progressive symmetric erythrokeratoderma (PSEK) phenotypes.

Methods: We performed whole-exome sequencing in a large cohort of people with EDD, including PPK and PSEK phenotypes, to identify novel genetic variants. We investigated the variant consequence using in silico predictions, assays in patient keratinocytes, high-resolution spatial transcriptomics and quantitative cytokine profiling.

Results: We identified three unrelated kindreds with autosomal dominant transmission of heterozygous SLURP1 variants affecting the same amino acid within the signal peptide (c.65C > A, p.A22D and c.65C > T, p.A22V). One (p.A22V) had isolated PPK; the other two (p.A22D) had PSEK and PPK. In silico modelling suggested that both variants alter pro-SLURP1 cleavage, appending two amino acids to the secreted protein, which we subsequently confirmed with mass spectrometry. In patient keratinocytes we found increased differentiation-induced SLURP1 expression and secretion compared to healthy control cells. Spatial transcriptomics revealed increased nuclear factor-κB (NF-κB) signalling and innate immune activity, which may contribute to epidermal hyperproliferation in dominant SLURP1-PPK/PSEK.

Conclusions: Our results expand the phenotypic spectrum of EDD due to SLURP1 pathogenic variants. While autosomal recessive Mal de Meleda is due to biallelic loss-of-function SLURP1 variants, our finding of autosomal dominant SLURP1 pathogenic variants in kindreds with PPK and PSEK suggests a novel mechanism of action. We found that heterozygous p.A22V and p.A22D SLURP1 variants append two amino acids to secreted SLURP1, increase differentiation-induced SLURP1 expression and secretion and upregulate NF-κB signalling in people with PSEK.