title: The elusive gene for keratolytic winter erythema.
abstract: Keratolytic winter erythema (KWE), also known as Oudtshoorn skin disease, is characterised by a cyclical disruption of normal epidermal keratinisation affecting primarily the palmoplantar skin with peeling of the palms and soles, which is worse in the winter. It is a rare monogenic, autosomal dominant condition of unknown cause. However, due to a founder effect, it occurs at a prevalence of 1/7 200 among South African Afrikaans-speakers. In the mid-1980s, samples were collected from affected families for a linkage study to pinpoint the location of the KWE gene. A genome-wide linkage analysis, using microsatellite markers, identified the KWE critical region on chromosome 8p23.1-p22. Subsequent genetic studies focused on screening candidate genes in this critical region; however, no pathogenic mutations that segregated exclusively with KWE were identified. The cathepsin B (CTSB) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) genes revealed no potentially pathogenic variants, nor did they show differential gene expression in affected skin. Mutation detection in additional candidate genes also failed to identify the KWE-associated variant, suggesting that the causal variant may be in an uncharacterised functional region. Bioinformatic analysis revealed highly conserved regions within the KWE critical region and a custom tiling array was designed to cover this region and to search for copy number variation. Although the study did not identify a variant that segregates exclusively with KWE, it provided valuable insight into the complex KWE-linked region. Next-generation sequencing approaches are being used to comb the region, but the causal variant for this interesting hyperkeratotic palmoplantar phenotype still remains elusive.
authors.affiliation: Division of Dermatology, Department of Medicine, Royal University Hospital, University of Saskatchewan, Canada. peter.hull@usask.ca.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hull
authors.forename: Angela
authors.initials: A
authors.lastname: Hobbs
authors.forename: Shaun
authors.initials: S
authors.lastname: Aron
authors.forename: Michele
authors.initials: M
authors.lastname: Ramsay
mesh_terms: D019295:Computational Biology; D056915:DNA Copy Number Variations; D004890:Erythema / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007642:Keratosis / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D010241:Parakeratosis / Q000473:pathology; D012873:Skin Diseases, Genetic / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D013019:South Africa