CLONING OF TABBY, THE MURINE HOMOLOG OF THE HUMAN EDA GENE - EVIDENCEFOR A MEMBRANE-ASSOCIATED PROTEIN WITH A SHORT COLLAGENOUS DOMAIN

X-Linked hypohidrotic ectodermal dysplasia (XLHED) is a human congenit al disorder resulting in abnormal tooth, hair and sweat gland developm ent. A candidate gene for the disorder has been cloned, but the functi on and full size of its putative protein product is unclear. We have i dentified a candidate cDNA for the mouse Tabby gene (Ta), which, based on phenotype and syntenic mapping, is postulated to represent the ana logous murine disorder, Mutations have been identified in three differ ent Ta alleles and Northern analysis indicates that the gene is expres sed at increasing levels during embryogenesis (11-17 days p.c.), the p eriod when affected structures develop, The putative protein product e ncoded by exon 1 is highly homologous (87% identical) to the predicted EDA protein product (135 amino acids), including the presence of a si ngle transmembrane domain. However, the murine cDNA also encodes an ad ditional 246 amino acids, which contains a short collagenous domain (G ly-X-Y)(19). This predicted structure is similar to a number of membra ne-associated proteins with either single or multiple collagenous doma ins in their extracellular C-terminal regions, Since mutations can onl y be identified in 10-15% of families with XLHED, it is likely that ad ditional 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 protei n may play a key role in epithelial-mesenchymal interactions, defects of which are thought to underlie the Ta/XLHED phenotype.