A signal peptide variant in SLURP1 with dominant-negative effect causes progressive symmetric erythrokeratodermia

Progressive symmetric erythrokeratodermia (PSEK) is a group of hereditary cornification disorders characterized by symmetrical, progressive erythroderma and hyperkeratosis over the body. Loss-of-function variants in SLURP1, encoding secreted Ly-6/uPAR-related protein 1, is known to cause Mal de Meleda, an autosomal recessive palmoplantar keratoderma.

To identify the genetic basis and the pathogenesis of a sporadic patient with PSEK.

Whole-exome sequencing and Sanger sequencing were performed to identify the pathogenic variant(s). The expression of SLURP1 was assessed on the patient's skin tissue by immunofluorescence. Western blotting (WB) and immunofluorescence (IF) were performed on eukaryotic overexpression systems to evaluate the signal peptide (SP) cleavage, subcellular localization and secretion of the mutant SLURP1. Combined WB and IF analyses were conducted on cells co-transfected with FLAG-tagged wild-type SLURP1 and untagged SLURP1-Ala22Asp.

We identified a de novo heterozygous variant in SLURP1 (c.65A > C, p.Ala22Asp) affecting the first residue before SP cleavage site in a patient with PSEK. This variant abolished the cleavage site of SP, resulting in translocation deficiency to the Golgi apparatus and decreased secretion of the mutant SLURP1. We also found that the SLURP1-Ala22Asp exerted a dominant-negative effect by impeding the SP cleavage of the wild-type SLURP1 and affecting its subcellular localization and secretion in a dose-dependent manner.

We reported the first autosomal-dominant variant in SLURP1 associated with a new phenotype of PSEK in a patient, emphasizing the genetic and clinical heterogeneity of SLURP1-associated genodermatoses.