The desmosomal cadherins comprise the desmocollins and desmogleins and are involved in epithelial cell-cell adhesion. There are three desmocollins (DSC 1-3) and three desmogleins (DSG 1-3) that are expressed in a tissue- and development-specific manner. Desmosomal proteins have been implicated in a number of disorders characterized by loss of cell-cell adhesion and trauma-induced skin fragility. Therefore, the desmocollins are potential candidates for genodermatoses involving epithelial tissues. In order to screen the entire DSC1 and DSC3 genes, we have characterized their intron-exon organization. The DSC1 gene comprises 17 exons spanning approximately 33 kb on 18q12.1, and the DSC3 gene comprises 17 exons spanning approximately 49 kb on 18q12.1. We have also developed a comprehensive PCR-based mutation detection strategy for desmocollins 1, 2, and 3 using primers placed on flanking introns followed by direct sequencing of the PCR products.