Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 606603

EDAR-ASSOCIATED DEATH DOMAIN; EDARADD

HGNC Approved Gene Symbol: EDARADD

Cytogenetic location: 1q42.3-q43 Genomic coordinates (GRCh38) : 1:236,348,259-236,484,930 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

EDARADD is a death domain adaptor which interacts with the death domain of EDAR (604095) and links the receptor to downstream signaling pathways.

Cloning and Expression

Headon et al. (2001) searched for the mutation responsible for the mouse 'crinkled' phenotype, a phenocopy of hypohidrotic ectodermal dysplasia identical to that of edar ('downless') and eda (see 305100; 'Tabby') mutants. The mouse and human EDARADD proteins are 80% identical with almost complete identity in the death domain, which is located in the carboxy terminus and is similar to the death domain of MyD88 (602170), a cytoplasmic transducer of Toll/interleukin receptor signaling. EDARADD also contains a Traf-binding consensus sequence.

Mapping

Based on sequence similarity with a BAC, Headon et al. (2001) mapped the EDARADD gene to chromosome 1q42.2-q43, a region for which conservation of synteny with the crinkled region of mouse chromosome 13 had been established.

Gene Function

Headon et al. (2001) found that EDARADD and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth and that EDARADD self-associates, a property common to many death domain proteins. Overexpression of EDARADD in HEK293T cells resulted in an NF-kappa-B (see 164011) reporter gene activation in a dose-dependent manner. Headon et al. (2001) found that EDAR is activated by EDA and uses EDARADD as an adaptor to build an intracellular signal-transducing complex. This linear pathway explains the identical phenotypes of the Tabby, downless, and crinkled mutants, and also the genetic heterogeneity of human hypohidrotic ectodermal dysplasia.

Molecular Genetics

In affected members of a consanguineous family with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD11B; 614941), Headon et al. (2001) identified a homozygous mutation in the EDARADD gene (606603.0001).

Bal et al. (2007) identified a heterozygous mutation in the EDARADD gene (606603.0002) in affected members of a Moroccan family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD11A; 614940). Functional expression studies showed that this mutation and the mutation identified by Headon et al. (2001) decreased NF-kappa-B activation and interfered with EDARADD interaction with EDAR and other EDARADD molecules, although to different degrees. Thus, mutations in the EDARADD gene can lead to both inherited forms of the disorder, indicating a common pathogenic pathway.

In a 3-generation German family with HED, Wohlfart et al. (2016) identified heterozygosity for a missense mutation in the EDARADD gene (D123N; 606603.0003) that segregated fully with disease and was not found in the ExAC database.

In 2 sisters with HED from a consanguineous Indian family, Chaudhary et al. (2016) identified homozygosity for a splice site mutation (606603.0004) that segregated with disease in the family and was not found in 101 ethnically matched controls or public databases.

Animal Model

The mouse 'crinkled' phenotype results from a genomic deletion of the Edaradd coding region (Headon et al., 2001).

Ohazama et al. (2004) found that Edaradd mutant mice had small enamel knots similar to those seen in Eda mutant mice. Enamel knots were not visible histologically and the expression of Shh (600725) was correspondingly reduced. Ohazama et al. (2004) concluded that Edaradd is essential in cusp formation.

Kuramoto et al. (2011) found a loss-of-function missense mutation in the death domain of the Edaradd gene in the sparse-and-wavy (swh) mutant rat. The swh/swh rat shows sparse and wavy hair, hypoplastic mammary glands, hypoplastic sebaceous glands, and abnormal tooth morphology. Kuramoto et al. (2011) considered the swh rat a model of hypohidrotic ectodermal dysplasia.

ALLELIC VARIANTS 4 Selected Examples):

.0001 ECTODERMAL DYSPLASIA 11B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL RECESSIVE

EDARADD, GLU142LYS
SNP: rs74315309, gnomAD: rs74315309, ClinVar: RCV000004407, RCV001729334, RCV004798715

In a large consanguineous family with hypohidrotic ectodermal dysplasia (ECTD11B; 614941) previously reported by Munoz et al. (1997), Headon et al. (2001) identified a G-to-A transition at nucleotide 424 of the EDARADD gene, resulting in a glutamate-to-lysine substitution at amino acid 142 (E142K) in the EDARADD death domain. This mutation was found in homozygosity. The glu-to-lys mutation alters the charge of an amino acid that is conserved between mouse and human EDARADD, as well as between the MyD88 and the Pfam death domain consensus sequence. This mutation cosegregated with the hypohidrotic ectodermal dysplasia phenotype, with all affected individuals displaying homozygosity for the mutation.

In functional expression studies in HEK293T cells, Bal et al. (2007) showed that the mutant E142K protein impaired NF-kappa-B activation by about 50%.

.0002 ECTODERMAL DYSPLASIA 11A, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL DOMINANT

EDARADD, LEU112ARG
SNP: rs121908116, ClinVar: RCV000004408, RCV000055985

In 7 affected members of a large Moroccan family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD11A; 614940), Bal et al. (2007) identified a heterozygous 335T-G transversion in exon 6A of the EDARADD gene, resulting in a leu112-to-arg (L112R) substitution in the death domain of the protein. Functional expression studies in HEK293T cells showed that the mutant L112R protein severely impaired NF-kappa-B activation and acted in a dominant-negative manner.

.0003 ECTODERMAL DYSPLASIA 11B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL DOMINANT

EDARADD, ASP123ASN
SNP: rs879255629, ClinVar: RCV000239549, RCV003765486

In a 16-year-old German girl with hypohidrotic ectodermal dysplasia (ECTD11A; 614940) and her affected mother and maternal grandfather, Wohlfart et al. (2016) identified heterozygosity for a c.367G-A transition (c.367G-A, NM_145861.2) in the EDARADD gene, resulting in an asp123-to-asn (D123N) substitution within the death domain. The mutation was not found in the proband's unaffected brother, father, and maternal grandmother, or in the ExAC database. Functional analysis indicated that although the mutant protein had similar binding ability to wildtype, activation of NFKB (see 164011) was severely impaired with the mutant.

.0004 ECTODERMAL DYSPLASIA 11B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL RECESSIVE

EDARADD, IVS2DS, G-A, +1
SNP: rs879255553, ClinVar: RCV000239464

In 2 sisters from a consanguineous Indian family with hypohidrotic ectodermal dysplasia (ECTD11B; 614941), Chaudhary et al. (2016) identified homozygosity for a splice site mutation in intron 2 (c.120+1G-A, NM_145861.2) of the EDARADD gene, predicted to inhibit splicing of exon 2. The mutation was not found in their unaffected father, in 101 ethnically matched controls, or in the ExAC database; DNA from their mother was unavailable. Analysis of minigene transcripts in HeLa and HEK293T cells revealed the generation of 2 aberrant transcripts with the mutant, which DNA sequencing showed to have arisen due activation of 2 alternate cryptic 5-prime splice sites. The major aberrant transcript was predicted to cause an altered reading frame, resulting in a premature termination codon located 2 nucleotides upstream of the 3-4 exon junction, whereas the minor transcript would include only 3 of 20 amino acids encoded by exon 2.

REFERENCES

1. Bal, E., Baala, L., Cluzeau, C., El Kerch, F., Ouldim, K., Hadj-Rabia, S., Bodemer, C., Munnich, A., Courtois, G., Sefiani, A., Smahi, A.Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus. Hum. Mutat. 28: 703-709, 2007. [PubMed: 17354266] [Full Text: https://doi.org/10.1002/humu.20500\]
2. Chaudhary, A. K., Girisha, K. M., Bashyam, M. D.A novel EDARADD 5-prime-splice site mutation resulting in activation of two alternate cryptic 5-prime-splice sites causes autosomal recessive hypohidrotic ectodermal dysplasia. (Letter) Am. J. Med. Genet. 170A: 1639-1641, 2016. [PubMed: 26991760] [Full Text: https://doi.org/10.1002/ajmg.a.37607\]
3. Headon, D. J., Emmal, S. A., Ferguson, B. M., Tucker, A. S., Justice, M. J., Sharpe, P. T., Zonana, J., Overbeek, P. A.Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 414: 913-916, 2001. [PubMed: 11780064] [Full Text: https://doi.org/10.1038/414913a\]
4. Kuramoto, T., Yokoe, M., Hashimoto, R., Hiai, H., Serikawa, T.A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene. BMC Genetics 12: 91, 2011. Note: Electronic Article. [PubMed: 22013926] [Full Text: https://doi.org/10.1186/1471-2156-12-91\]
5. Munoz, F., Lestringant, G., Sybert, V., Frydman, M., Alswaini, A., Frossard, P. M., Jorgenson, R., Zonana, J.Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder. Am. J. Hum. Genet. 61: 94-100, 1997. [PubMed: 9245989] [Full Text: https://doi.org/10.1086/513905\]
6. Ohazama, A., Courtney, J.-M., Tucker, A. S., Naito, A., Tanaka, S., Inoue, J.-I., Sharpe, P. T.Traf6 is essential for murine tooth cusp morphogenesis. Dev. Dyn. 229: 131-135, 2004. [PubMed: 14699584] [Full Text: https://doi.org/10.1002/dvdy.10400\]
7. Wohlfart, S., Soder, S., Smahi, A., Schneider, H.A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia. Am. J. Med. Genet. 170A: 249-253, 2016. [PubMed: 26440664] [Full Text: https://doi.org/10.1002/ajmg.a.37412\]

Contributors:

Marla J. F. O'Neill - updated : 08/09/2016
Joanna S. Amberger - updated : 11/20/2012
Cassandra L. Kniffin - updated : 8/20/2007
Gregory S. Antonarakis - updated : 9/13/2005

Creation Date:

Ada Hamosh : 1/9/2002

Edit History:

carol : 08/09/2016
terry : 11/20/2012
carol : 11/20/2012
carol : 11/20/2012
joanna : 11/15/2012
terry : 6/18/2012
joanna : 10/7/2008
wwang : 9/5/2007
ckniffin : 8/20/2007
alopez : 6/18/2007
carol : 9/13/2005
terry : 3/17/2005
alopez : 2/4/2002
alopez : 1/9/2002