Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency

Recently, the first example of a human mutation in the gene encoding the de smosomal plaque protein, desmoplakin, has been described in a patient with autosomal dominant striate palmoplantar keratoderma. We now report a furthe r case of desmoplakin mutation in a proband with striate palmoplantar kerat oderma that also results in a null allele and haploinsufficiency. The mutat ion was a heterozygous G>A transition at the donor +1 site of intron 7 of t he desmoplakin gene (939+1 G>A; Genbank M77830). The aberrant splicing lead s to retention of the entire intron 7, which contains a premature terminati on codon within the N-terminal domain of the peptide. Because the mutant nu ll allele could not be identified on cDNA sequencing, we determined by poly merase chain reaction the exon-intron organization of the desmoplakin gene to facilitate analysis of genomic DNA. The gene spans approximately 45 kb o f chromosome 6 and comprises 24 exons ranging in size from 51 bp to 3922 bp , We have also characterized fully the 3'UTR of the desmoplakin cDNA. This study demonstrates the relevance of haploinsufficiency for desmoplakin in t he pathogenesis of this genodermatosis. Assessment of family members bearin g the mutant allele also emphasizes the significance of an individual's age and exposure to skin trauma in manifesting full phenotypic expression of t he disorder.