EDAR

Ectodysplasin-A receptor (EDAR, also DL or downless) is the specific type I transmembrane receptor of the TNF receptor superfamily that transduces signals from ectodysplasin-A1 (EDA-A1) during ectodermal organ development. Its extracellular region comprises two complete and one partial cysteine-rich domains that engage the trimeric EDA-A1 ligand, while its cytoplasmic death domain is structurally divergent from apoptosis-mediating death domains and instead constitutively associates with the adaptor EDARADD. Ligand-induced EDAR clustering nucleates an EDAR-EDARADD complex that activates the canonical IKK-NF-κB and JNK cascades, instructing the initiation, branching and differentiation of hair follicles, teeth (via epithelial placode and enamel knot formation), sweat glands and other ectodermal appendages. EDAR mutations cause autosomal dominant and recessive hypohidrotic ectodermal dysplasia; a gain-of-function EDAR variant (V370A) common in East Asian populations increases hair thickness, eccrine sweat gland density and shoveling of incisors, a textbook example of recent positive selection in human evolution.