Death domains, dysplasia and development

Edar is a member of the tumour-necrosis factor receptor (TNFR) family of signalling molecules that contains an intracellular death-domain. Mutation of the mammalian downless gene encoding Edar, or Tabby which encodes its ligand Eda, results in ectodermal dysplasia and defective morphogenesis. In the December 20/27 Nature, Headon et al. report characterization of the protein encoded by the mouse crinkled locus, a mutation in which results in hypohidrotic dysplasia identical to Tabby and downless mutants (Nature 2001, 414:913-916).

They performed positional cloning of the crinkled (cr) gene from cr x Mus castaneous backcrosses. Comparison of the syntenic regions of the mouse and human genomes led to the identification of a gene encoding a death-domain adaptor protein, named EDARADD. The human EDARADD gene is mutated in patients with autosomal hypohidrotic ectodermal dysplasia. The Edaradd protein interacts with the intracellular domain of Edar and resulted in...