title: Exclusion of CTSB and FDFT1 as positional and functional candidate genes for keratolytic winter erythema (KWE).
abstract: BACKGROUND
  Keratolytic winter erythema (KWE) or Oudtshoorn skin disease is a rare autosomal dominant monogenic disorder of epidermal keratinisation characterized clinically by cyclical peeling of the palms and soles. Due to a founder effect many KWE families have been identified in South Africa and the gene has been localized to 8p23.1-22, but the causal gene has yet to be identified.
  
  
  OBJECTIVE
  To examine two compelling positional and functional candidate genes within the critical region on 8p: cathepsin B (CTSB), a lysosomal cysteine protease localized to pericellular spaces between keratinocytes, possibly playing a role in cell-cell adhesion; and farnesyl-diphosphate farnesyltransferase (FDFT1), a membrane-associated enzyme in cholesterol biosynthesis which, among its many functions, plays a role in barrier permeability and integrity.
  
  
  METHODS
  Mutation screening of the coding regions, 5'UTRs and intron/exon boundaries of CTSB and FDFT1 in genomic DNA and cDNA of patients affected with KWE. Relative gene expression profiles of CTSB and FDFT1 in palmoplantar skin biopsies were assessed by real-time RT-PCR.
  
  
  RESULTS
  No DNA variants that segregate exclusively with KWE were identified. There was no significant difference in the CTSB expression profiles but a trend towards increased expression of FDFT1 was observed in the skin of affected individuals (p=0.063). This observation prompted analysis of the FDFT1 promoter region; however, no genetic variants segregating with the KWE phenotype were observed and it is likely that the increased expression was triggered in response to skin inflammation and peeling.
  
  
  CONCLUSIONS
  CTSB and FDFT1 are excluded as candidates for KWE.
authors.affiliation: Division of Human Genetics, School of Pathology, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Angela
authors.initials: A
authors.lastname: Hobbs
authors.forename: Shaun
authors.initials: S
authors.lastname: Aron
authors.forename: Sian
authors.initials: S
authors.lastname: Hartshorne
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hull
authors.forename: Michèle
authors.initials: M
authors.lastname: Ramsay
mesh_terms: D020121:5' Untranslated Regions; D002401:Cathepsin B / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002898:Chromosomes, Human, Pair 8; D004252:DNA Mutational Analysis; D004890:Erythema / Q000235:genetics* / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000096:biosynthesis* / Q000235:genetics; D018703:Founder Effect; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D014644:Genetic Variation; D006801:Humans; D007642:Keratosis / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000378:metabolism; D013019:South Africa
chemical_list: D020121:5' Untranslated Regions; D013186:Farnesyl-Diphosphate Farnesyltransferase; C533912:CTSB protein, human; D002401:Cathepsin B