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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.

Pubmed ID: 11882293


  • Yan M
  • Zhang Z
  • Brady JR
  • Schilbach S
  • Fairbrother WJ
  • Dixit VM


Current biology : CB

Publication Data

March 5, 2002

Associated Grants


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