Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma

The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1 . Recently we have identified a mutation in the DSG1 gene coding for desmog lein 1 as the cause of the autosomal dominant skin disease striate palmopla ntar keratoderma (SPPK) in which affected individuals have marked hyperkera totic bands on the palms and soles. In the present study we present the com plete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leadi ng to a truncated protein, due either to an addition or deletion of a singl e base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fo urth extracellular domains, and one was in exon 2 coding for part of the pr osequence of this processed protein. This latter mutation thus results in t he mutant allele synthesising only 25 amino acid residues of the prosequenc e of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. Th e most severe consequences of SPPK mutations are in regions of the body whe re pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal f unction.