A Missense Mutation in the Death Domain of EDAR Abolishes the Interaction with EDARADD and Underlies Hypohidrotic Ectodermal Dysplasia

<i>Background:</i> Hypohidrotic ectodermal dysplasia (HED) is a rare condition characterized by hypotrichosis, hypohidrosis and hypodontia. The disease shows X-linked recessive, autosomal-dominant or autosomal-recessive inheritance trait. X-linked form of HED is caused by mutations in the <i>EDA</i> gene, while autosomal forms are caused by mutations in either <i>EDAR</i> or <i>EDARADD </i>genes. <i>Methods:</i> We analyzed the DNA from a Japanese patient with HED through direct sequencing, and also performed functional studies for the mutation. <i>Results:</i> We identified a homozygous missense mutation c.1073G>A (p.R358Q) in the <i>EDAR</i> gene of the patient, which was a nonconservative amino acid substitution within the death domain of EDAR protein. We demonstrated that the p.R358Q mutant EDAR protein lost its affinity to EDARADD, leading to reduced activation of the downstream NF-ĸB. <i>Conclusion:</i> Our data further suggest the crucial role of the EDAR signaling in development of hair, teeth, and sweat gland in humans.