Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus

Abstract

Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectodermal differentiation characterized by sparse hair, abnormal or missing teeth, and inability to sweat. X-linked EDA is the most common form, caused by mutations in the EDA gene, which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) family. Autosomal dominant and recessive forms of EDA have been also described and are accounted for by two genes. Mutations in EDAR, encoding a TNF receptor (EDAR) cause both dominant and recessive forms. In addition, mutations in a recently identified gene, EDARADD, encoding EDAR-associated death domain (EDARADD) have been shown to cause autosomal recessive EDA. Here, we report a large Moroccan family with an autosomal dominant EDA. We mapped the disease gene to chromosome 1q42.2-q43, and identified a novel missense mutation in the EDARADD gene (c.335T>G, p.Leu112Arg). Thus, the EDARADD gene accounts for both recessive and dominant EDA. EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). We compared the functional consequences of the dominant (p.Leu112Arg) and recessive mutation (p.Glu142Lys), which both occurred in the death domain (DD) of EDARADD. We demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation, whereas the p.Glu142Lys retained the ability to significantly activate the NF-kB pathway. The p.Leu112Arg mutation is probably a dominant negative form as its cotransfection impaired the wild-type EDARADD's ability to activate NF-kB. Our results confirm that NF-kB activation is impaired in EDA and support the role of EDARADD DD as a downstream effector of EDAR signaling.

Mutation p.Leu354Pro in EDA causes severe hypohidrotic ectodermal dysplasia in a Chinese family

“…implicated in oncogenesis and several developmental processes associated with HED/EDA (Bal et al, 2007;Headon et al, 2001;Cluzeau et al, 2011).…”

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

“…In most cases, HED shows an X-linked recessive inheritance pattern (OMIM 305100) while a minority of HED is inherited as an autosomal-dominant (OMIM 129490) or autosomal-recessive trait (OMIM 224900). It has been shown that X-linked HED is caused by mutations in the EDA gene [1], while autosomal forms of HED are caused by mutations in either the EDAR [2] or the EDARADD [3,4] genes. The EDA gene encodes various isoforms of a type II transmembrane protein through alternative splicing [5,6,7].…”

Mutations inEDARADDaccount for a small proportion of hypohidrotic ectodermal dysplasia cases

“…Mutations in EDAR (2q11-q13, MIM 604095), which encodes the EDA receptor (EDAR, a TNF receptor) can cause either dominant or recessive forms, and is mutated in approximately 25% of non-EDA-related HED. [6][7][8][9][10][11][12][13][14] Mutations in the EDARADD gene (1q42-q43, MIM 606603), which encodes the EDAR-associated death domain (EDARADD), have been shown to cause either autosomal recessive or dominant HED. However, only two HED families with EDARADD mutations have been reported to date, 13,14 and the incidence of EDARADD mutations in HED remains unknown.…”

“…The dominant one is thought to act by a dominant negative effect, as it interferes with wild-type EDARADD. 13 We have screened for EDARADD mutations 28 HED patients in whom mutations in both the EDA and EDAR genes were excluded by direct sequencing. 7 We identified only one mutation, a 6-bp homozygous in-frame deletion, demonstrating that EDARADD is rarely implicated in HED patients (one of 136 of the initial cohort, < 1%).…”