Autosomal dominant SLURP1 variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma

Summary: Abstract Body: Epidermal differentiation disorders (EDDs) are severe skin conditions characterized by localized or generalized skin scaling and erythema often due to damaging single-gene variants. We performed whole exome sequencing in a large cohort with EDD including palmoplantar keratoderma (PPK) and progressive symmetric erythrokeratoderma (PSEK) phenotypes to identify novel genetic variants. We investigated the consequence of these variants using in silico predictions, assays in primary patient keratinocytes, and high-resolution spatial transcriptomics and quantitative cytokine profiling in affected skin. We identified three unrelated kindreds with autosomal dominant transmission of heterozygous variants in SLURP1 at the same amino acid position (c.65C>A, p.A22D, and c.65C>T, p.A22V) within the signal peptide sequence. One (p.A22V) had isolated PPK, and two others (p.A22D) had a PSEK phenotype. In silico modeling suggested that variants altered the cleavage site of pro-SLURP1, appending two amino acids to the secreted protein, subsequently confirmed with mass spectrometry of secreted mutant protein. Assays in primary patient keratinocytes revealed that differentiation-induced SLURP1 expression and secretion was increased in patient cells compared to healthy control cells. Spatial transcriptomics in affected tissue confirmed increased SLURP1 expression in suprabasal epidermis and showed increased NF-κB signaling and innate immune activity. Our results expand the phenotypic spectrum of EDD due to pathogenic variants in SLURP1. Xingyuan Jiang¹, Ryland D. Mortlock^{1, 2}, Jing Zhou¹, Ronghua Hu¹, Ivan Lomakin¹, Christopher G. Bunick¹, Keith Choate^{1, 2, 3} 1. Dermatology, Yale University School of Medicine, New Haven, CT, United States. 2. Genetics, Yale University School of Medicine, New Haven, CT, United States. 3. Pathology, Yale University School of Medicine, New Haven, CT, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics