Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency

Recently, the first example of a human mutation in the gene encoding the desmosomal plaque protein, desmoplakin, has been described in a patient with autosomal dominant striate palmoplantar keratoderma. We now report a further case of desmoplakin mutation in a proband with striate palmoplantar keratoderma that also results in a null allele and haploinsufficiency. The mutation was a heterozygous G>A transition at the donor +1 site of intron 7 of the desmoplakin gene (939+1 G>A; Genbank M77830). The aberrant splicing leads to retention of the entire intron 7, which contains a premature termination codon within the N-terminal domain of the peptide. Because the mutant null allele could not be identified on cDNA sequencing, we determined by polymerase chain reaction the exon-intron organization of the desmoplakin gene to facilitate analysis of genomic DNA. The gene spans approximately 45 kb of 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 the pathogenesis of this genodermatosis. Assessment of family members bearing the mutant allele also emphasizes the significance of an individual's age and exposure to skin trauma in manifesting full phenotypic expression of the disorder.