Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma

Epidermal differentiation disorders (EDDs, a.k.a. ichthyosis and palmoplantar keratoderma) are severe heritable skin conditions characterized by localized or generalized skin scaling and erythema. To identify novel genetic variants causing palmoplantar keratoderma (PPK) and progressive symmetric erythrokeratoderma (PSEK) phenotypes. We performed whole exome sequencing in a large EDD cohort 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. 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, and two others (p.A22D) had PSEK and PPK. In silico modeling 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 NF-κB signaling and innate immune activity which may contribute to epidermal hyperproliferation in dominant SLURP1-PPK/PSEK. 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 signaling in PSEK cases.