The identification and characterization of the causative gene for Keratolytic winter erythema in South African families

Abstract

Keratolytic winter erythema (KWE) or Oudtshoorn skin disease is a rare monogenic autosomal dominant condition with an unknown cause. KWE is a disorder of epidermal keratinisation that involves the necrobiosis of the Malpigihian layer of the palmoplantar skin with the consequent dissection of the stratum corneum. This cutaneous disorder was first described by Findlay et al. (1977) and occurs with a high prevalence of 1/7200 in the South African Afrikaans-speaking white population and with a lower, but unspecified prevalence in the Coloured population. The primary objective of this study was to identify and characterise the causative gene for KWE, by examining plausible positional candidate genes. The KWE gene has been localized to chromosome 8p23.1-p22 in a region of 1.2 Mb. In order to identify a potentially causative KWE mutation, the coding regions of each candidate gene was sequenced from genomic DNA. Each of the genetic variants identified was also observed in the control group or had previously been shown to be polymorphic, eliminating them all from causing KWE. The cDNA of the two most likely candidates, FDFT1 and CTSB, was sequenced in order to identify deep intronic variants that might affect splicing and that would not be identified at a genomic DNA level. No such variation was observed. The relative expression profiles of CTSB and FDFT1 in affected and non-affected palmoplantar skin was analysed using real-time RT-PCR. The relative expression of CTSB in the skin of patients did not differ significantly from controls (p=0.68). However, a trend was observed towards increased expression of FDFT1 in the skin of KWE affected individuals (p=0.063). This observation prompted the analysis of the FDFT1 promoter region through genomic sequencing. No genetic variants identified within the promoter region segregated with the KWE phenotype. The increased FDFT1 expression is therefore unlikely to result from a mutation within the promoter region of this gene and may be in response to the disruption of the epidermal barrier in affected skin. There is a strong correlation between the severity of the KWE phenotype and the level of FDFT1 expression. Although none of the chosen positional candidate genes appear to harbour the KWE-causing mutation, they can be excluded from the list of possible positional candidates for KWE, taking us one step closer to discovering the molecular cause of KWE.