X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common of the ectodermal dysplasias, results in the abnormal development of teeth, hair, and eccrine sweat glands. The gene responsible for this disorder, EDA1, was identified by isolation of a single cDNA that was predicted to encode a 135-amino-acid protein. Mutations in this splice form were detected in <10% of families with XLHED. The subsequent cloning of the murine homologue of the EDA1 gene (Tabby [Ta]) allowed us to identify a second putative isoform of the EDA1 protein (isoform II) in humans. This EDA1 cDNA is predicted to encode a 391-residue protein, of which 256 amino acids are encoded by the new exons. The putative protein is 94% identical to the Ta protein and includes a collagen-like domain with 19 repeats of a Gly-X-Y motif in the presumptive extracellular domain. The genomic structure of the EDA1 gene was established, and the complete sequence of the seven new exons was determined in 18 XLHED- affected males. Putative mutations, including 12 missense, one nonsense, and four deletion mutations, were identified in ~95% of the families. The results suggest that EDA1 isoform II plays a critical role in tooth, hair, and sweat gland morphogenesis, whereas the biological significance of isoform I remains unclear. Identification of mutations in nearly all of the XLHED families studied suggests that direct molecular diagnosis of the disorder is feasible. Direct diagnosis will allow carrier detection in families with a single affected male and will assist in distinguishing XLHED from the rarer, clinically indistinguishable, autosomal recessive form of the disorder.
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