THE ANHIDROTIC ECTODERMAL DYSPLASIA GENE (EDA) UNDERGOES ALTERNATIVE SPLICING AND ENCODES ECTODYSPLASIN-A WITH DELETION MUTATIONS IN COLLAGENOUS REPEATS

Anhidrotic ectodermal dysplasia (EDA) is an X-linked recessive disorde r which affects ectodermal structures. A cDNA encoding a 135 amino aci d protein with mutations in 5-10% of EDA patients has been reported. W e have built up a complete splicing map of the EDA gene and characteri zed the longest and what most probably represents the full-length EDA transcript, EDA-A, It encodes a 391 amino acid transmembrane protein w ith a short collagenous domain, (Gly-X-Y)(19), and is highly homologou s to the protein mutated in Tabby mice (Ta-A), Four new transcripts th at code for truncated proteins lacking the collagenous domain were als o detected. The splice variants show different expression patterns in eight tissues analyzed, suggesting a regulatory mechanism for gene exp ression. The EDA-A form of the protein is transported to the cell memb rane and induces rounding of the cells, properties also associated wit h the 135 amino acid isoform, We have determined the genomic organizat ion and the exon-intron boundaries of the EDA gene. SSCP analysis of t he nine exons corresponding to EDA-A allowed the identification of mut ations in 12 out of 15 EDA patients. Interestingly, three mutations re moved either two or four of the Gly-X-Y repeats without interrupting t he reading frame, thus suggesting a functional role for the collagenou s domain. Our results will allow mutation diagnostics in the majority of patients.