Molecular Pathogenesis
The molecular pathogenesis of hypohidrotic ectodermal dysplasia (HED) is not fully understood. EDA, the gene responsible for X-linked HED, produces ectodysplasin-A, a protein that is important for normal development of ectodermal appendages including hair, teeth, and sweat glands. Evidence is accumulating that ectodysplasin-A is important in several pathways that involve ectodermal-mesodermal interactions during embryogenesis. Defects in the molecular structure of ectodysplasin-A may inhibit the action of enzymes necessary for normal development of the ectoderm and/or its interaction with the underlying mesoderm.
EDA
Gene structure.
EDA is an X-linked gene that comprises 12 exons, eight of which encode the transmembrane protein ectodysplasin-A [Bayés et al 1998, Ferguson et al 1998, Monreal et al 1998] (Reference sequence NM_001399.4). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Numerous pathogenic variants including nucleotide substitutions (missense, nonsense, and splicing), small deletions and insertions, and gross deletions have been identified in EDA [Visinoni et al 2003, Hsu et al 2004].
Normal gene product. Ectodysplasin-A has 391 amino acid residues with a short collagenous domain (Gly-X-Y) that is homologous to the protein encoded by the mouse gene Eda. Ezer et al [1999] demonstrated that ectodysplasin-A is a trimeric type II protein that colocalizes with cytoskeletal structures at the lateral and apical surfaces of cells, suggesting that it is a novel member of the tumor necrosis factor (TNF)-related ligand family that plays a role in early epithelial-mesenchyme interactions. Several isoforms of ectodysplasin are expressed in keratinocytes, hair follicles, and sweat glands (Reference sequence NP_001390.1).
Abnormal gene product. Pathogenic variants in EDA lead to ectodysplasin A molecules that are unable to regulate epithelial-mesenchyme interactions, resulting in abnormal ectodermal appendages. Several pathogenic variants in EDA produce ectodysplasin A molecules that resist cleavage by furin and are consequently unable to be converted to their active forms and mediate the cell-to-cell signaling that regulates morphogenesis of ectodermal appendages [Chen et al 2001].
EDAR
Gene structure. Human EDAR has 12 exons (NM_022336.3). EDAR is orthologous to the mouse gene Edar. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Several pathogenic variants have been identified in EDAR, including deletions, transitions, and a gross deletion [Monreal et al 1999, Shimomura et al 2004, Chassaing et al 2006, Mégarbané et al 2008, van der Hout et al 2008].
Table 2.
EDAR Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.803+1G>A | |
NM_022336.3
NP_071731.1
|
c.338G>A | p.Cys113Tyr |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
EDAR encodes a 448-amino acid protein that contains a single transmembrane domain with type 1 membrane topology. The protein probably functions as a multimeric receptor and is related to the TNFR family. It forms a ligand-receptor pair with ectodysplasin (NP_071731.1).
Abnormal gene product. The defective proteins encoded by pathogenic variants in EDAR are unable to bind with ectodysplasin. Those responsible for autosomal recessive HED exhibit loss of function, while those responsible for autosomal dominant HED exhibit a dominant negative effect [Valcuende-Cavero et al 2008]. At least two of the dominant negative pathogenic variants are not associated with the HED phenotype.
EDARADD
Gene structure. Human EDARADD has two isoforms, each with six exons encoding 205 and 215 amino acid proteins (NM_080738.3 and NM_145861.2, respectively). EDARADD is homologous to the mouse gene Edaradd. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. A missense variant has been identified in an inbred family with autosomal recessive HED [Headon et al 2001]. Another family with autosomal dominant HED has been found to have a heterozygous pathogenic variant in EDARADD, indicating that both recessive and dominant forms of HED can be caused by EDARADD pathogenic variants [Bal et al 2007]. A homozygous 6-bp in-frame deletion () has also been reported in an individual with HED [Chassaing et al 2010].
Table 3.
EDARADD Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.335T>G | p.Leu112Arg |
NM_080738.3
NP_542776.1
|
c.372_377del (402_407del) 1 | p.Thr125_Val126del (Thr135-Val136del) 1 |
c.424G>A | p.Glu142Lys |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. The protein encoded by EDARADD is similar to the death domain, MyD88, a cytoplasmic transducer of Toll/interleukin receptor signaling [Headon et al 2001]. It also contains a Traf-binding consensus sequence. It is coexpressed with tumor necrosis factor receptor superfamily member EDAR in epithelial cells during the formation of hair follicles and teeth. It interacts with the death domain of EDAR and links the receptor to signaling pathways downstream.
Abnormal gene product.
EDARADD pathogenic variants alter the charge of an amino acid in the protein, usually rendering it unable to interact with EDAR. In one family with autosomal dominant HED, a novel missense variant did not interfere with interaction between EDAR and EDARADD proteins but still lead to impaired activation of NF-kappa B signaling [Wohlfart et al 2016].
WNT10A
Gene structure.
WNT10A contains four exons and maps to chromosome 2q35 near WNT6.
Pathogenic variants. A nonsense variant is one of the most common WNT10A pathogenic variants. A missense variant is also very common. Multiple other missense and nonsense variants have been described [Bohring et al 2009, Cluzeau et al 2011, Mues et al 2014, Bergendal et al 2016].
Table 4.
WNT10A Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
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c.321C>A | p.Cys107Ter |
NM_025216.2
NP_079492.2
|
c.682T>A | p.Phe228Ile |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
WNT10A encodes a 417-amino acid peptide containing two N-linked glycosylation sites and residues conserved among WNTs. The protein contains two domains, a signal peptide and the Wnt domain and encodes a secreted signaling molecule that is involved in several developmental processes, such as regulation of cell fate and patterning during embryogenesis. WNT10A and WNT10B are highly expressed in embryonic skin as well as the placodes involved in follicle morphogenesis. WNT10A is also very important for normal dentinogenesis and tooth morphogenesis.
Abnormal gene product. The WNT signal transduction pathway is essential for the development of ectodermally derived tissues. Therefore, WNT10A pathogenic variants are associated with lack of normal development of the dentition most frequently, but also affect other ectodermal structures including sweat glands, hair and nails.