{"doi":"10.1093/bjd/ljaf049","title":"Autosomal dominant <i>SLURP1</i> variants cause palmoplantar keratoderma and progressive symmetric erythrokeratoderma","abstract":"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.","journal":"British Journal of Dermatology","year":2025,"id":540305,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":583134,"name":"Ryland D. Mortlock","orcid":"0000-0001-9666-4394","position":1,"is_corresponding":false},{"id":246110,"name":"Ivan B. Lomakin","orcid":"0000-0001-6528-5068","position":2,"is_corresponding":false},{"id":510299,"name":"Jing Zhou","orcid":"0000-0001-6601-4446","position":3,"is_corresponding":false},{"id":510300,"name":"Rong‐Hua Hu","orcid":"0000-0002-5260-2519","position":4,"is_corresponding":false},{"id":1428117,"name":"M Cossio","orcid":"0000-0003-0202-3954","position":5,"is_corresponding":false},{"id":354160,"name":"Christopher G. Bunick","orcid":"0000-0002-4011-8308","position":6,"is_corresponding":false},{"id":381677,"name":"Keith A. Choate","orcid":"0000-0003-1010-6354","position":7,"is_corresponding":false},{"id":1418136,"name":"Xingyuan Jiang","orcid":"0000-0002-9891-6353","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"39913669","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}