Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice.

Hypohydrotic Ectodermal Dysplasia (HED) is a genetic disease seen in humans and mice. It is characterized by loss of hair, sweat glands, and teeth. The predominant X-linked form results from mutations in ectodysplasin-A (EDA), a TNF-like ligand. A phenotypically indistinguishable autosomal form of the disease results from mutations in the ...
receptor for EDA (EDAR). EDAR is a NF-kappaB-activating, death domain-containing member of the TNF receptor family. crinkled, a distinct autosomal form of HED, was discovered in a mouse strain in which both the ligand (EDA) and receptor (EDAR) were wild-type, suggestive of a disruption further downstream in the signaling pathway. Employing a forward genetic approach, we have cloned crinkled (CR) and find it to encode a novel death domain-containing adaptor. crinkled binds EDAR through a homotypic death domain interaction and mediates engagement of the NF-kappaB pathway, possibly by recruiting TRAF2 to the receptor-signaling complex. This is an unprecedented example of naturally occurring mutations in ligand, receptor, or adaptor giving rise to the same phenotypic disease characterized by a defect in the proper development of epidermal appendages.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Cloning, Molecular, DNA, Complementary, Ectodermal Dysplasia, Edar Receptor, Edar-Associated Death Domain Protein, Exons, Fish Proteins, Humans, Ligands, Mice, Mice, Mutant Strains, Molecular Sequence Data, Mutation, NF-kappa B, Phenotype, Protein Structure, Tertiary, Proteins, Sequence Homology, Amino Acid, TNF Receptor-Associated Factor 2, Tissue Distribution
Curr. Biol.
Date: Mar. 05, 2002
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