X-Linked hypohidrotic ectodermal dysplasia (XLHED) is a human congenital disorder resulting in abnormal tooth, hair and sweat gland development. A candidate gene for the disorder has been cloned, but the function and full size of its putative protein product is unclear. We have identified a candidate cDNA for the mouse Tabby gene (Ta), which, based on phenotype and syntenic mapping, is postulated to represent the analogous murine disorder. Mutations have been identified in three different Ta alleles and Northern analysis indicates that the gene is expressed at increasing levels during embryogenesis (11-17 days p.c.), the period when affected structures develop. The putative protein product encoded by exon 1 is highly homologous (87% identical) to the predicted EDA protein product (135 amino acids), including the presence of a single transmembrane domain. However, the murine cDNA also encodes an additional 246 amino acids, which contains a short collagenous domain (Gly-X-Y)19. This predicted structure is similar to a number of membrane-associated proteins with either single or multiple collagenous domains in their extracellular C-terminal regions. Since mutations can only be identified in 10-15% of families with XLHED, it is likely that additional homologous exons exist for the human EDA gene. Hybridization of YACs from the EDA region with the Ta cDNA support this hypothesis. The predicted extracellular collagenous domain of this membrane protein may play a key role in epithelial-mesenchymal interactions, defects of which are thought to underlie the Ta/XLHED phenotype.