title: Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.forename: John Ridgway
authors.initials: JR
authors.lastname: Brady
authors.forename: Sarah
authors.initials: S
authors.lastname: Schilbach
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism*; D053339:Edar Receptor; D053362:Edar-Associated Death Domain Protein; D005091:Exons; D029941:Fish Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D047992:TNF Receptor-Associated Factor 2; D014018:Tissue Distribution
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; C506125:EDARADD protein, human; D053339:Edar Receptor; D053362:Edar-Associated Death Domain Protein; C506124:Edaradd protein, mouse; D029941:Fish Proteins; D008024:Ligands; D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; C438683:ectodysplasin-A receptor protein, Oryzias latipes