Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: EDA
SNOMEDCT: 239007005, 7731005;
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:69,616,113-70,039,472 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Ectodermal dysplasia 1, hypohidrotic, X-linked | 305100 | X-linked recessive | 3 |
| Tooth agenesis, selective, X-linked 1 | 313500 | X-linked dominant | 3 |
To identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA) (XHED; 305100), Srivastava et al. (1996) fine mapped the translocation breakpoint in an EDA patient with the translocation t(X;1)(q13.1;p36.3). They determined that the EDA candidate region contains 5 groups of rare-cutter restriction sites that define CpG islands. The third of these CpG islands mapped within less than 1 kb of the translocation breakpoint, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint. Northern blot analysis with a probe from this CpG island detected an mRNA of approximately 6 kb in several fetal tissues tested. Srivastava et al. (1996) concluded that the CpG island just proximal to the translocation breakpoint of their patient lies at the 5-prime end of a candidate gene for EDA.
Kere et al. (1996) reported the positional cloning of the EDA1 gene. From an adult sweat gland cDNA library, they identified a single cDNA representing a full-length transcript composed of 2 exons. The putative gene product was a 135-residue protein (isoform I) predicted to contain a single transmembrane domain. The gene was expressed in keratinocytes, hair follicles, sweat glands, and in other adult and fetal tissues. The authors suggested that the predicted EDA protein may belong to a novel class with a role in epithelial-mesenchymal signaling. In several patients with EDA, Kere et al. (1996) identified deletions and mutations in the EDA1 gene (see MOLECULAR GENETICS). Kere et al. (1996) and Ferguson et al. (1997) speculated that, since mutations in exon 1 could be identified in only 10 to 15% of families with EDA, it was likely that additional homologous exons existed.
Cloning of the murine homolog by Srivastava et al. (1997) and Ferguson et al. (1997) (see below) allowed the identification of a second putative isoform of the EDA1 protein (isoform II) in humans. This EDA1 cDNA was predicted to encode a 391-residue protein, of which 256 amino acids were encoded by the 'new' exons. The putative protein is 94% identical to the mouse homolog and includes a collagen-like domain with 19 repeats of a Gly-X-Y motif in the presumptive extracellular domain (Monreal et al., 1998).
Srivastava et al. (1997) cloned the mouse 'Tabby' (Ta) gene and identified 3 different transcript isoforms encoding proteins of 391, 177, and 220 amino acids. All shared the same exon 1, which showed 88% homology with the first 132 amino acids of human EDA. The predicted molecular mass of the 392-amino acid Ta form was 41.6 kD. Reciprocal comparative analysis of EDA and Ta sequences led to extension of the known span of the human gene. Srivastava et al. (1997) confirmed that the Ta gene was mutated in 2 independent Tabby mouse strains. They demonstrated that the gene was expressed in developing teeth and epidermis and found no expression in corresponding tissues from mutant Tabby mice. The authors suggested that the isoforms of ectodysplasin-A may correlate with differential roles during embryonic development.
Ferguson et al. (1997) identified a candidate cDNA for the mouse Ta gene, which, based on phenotype and syntenic mapping, was postulated to represent the murine equivalent of EDA. They found that the murine cDNA also encoded an additional 246 amino acids, which contained a short collagenous domain (Gly-X-Y)19. This predicted structure was similar to a number of membrane-associated proteins with either single or multiple collagenous domains in the extracellular C-terminal regions. Northern blot analysis showed that the gene was expressed at increasing levels during embryogenesis (11-17 days p.c.), the period when affected structures develop.
Bayes et al. (1998) constructed a complete splicing map of the EDA gene and characterized the longest and what probably represents the full-length EDA transcript, EDA-A, which encodes the 391-amino acid transmembrane protein. They also detected 4 new transcripts that coded for truncated proteins lacking the collagenous domain. The splice variants showed different expression patterns in 8 tissues analyzed, suggesting a regulatory mechanism for gene expression. Bayes et al. (1998) found that the full-length form of the protein is transported to the cell membrane and induces rounding of the cells, properties also associated with the 135-amino acid isoform.
Monreal et al. (1998) and Bayes et al. (1998) established the genomic structure of the EDA gene.
Ezer et al. (1999) showed that the sequence of the longest isoform encoded by the EDA gene includes an interrupted collagenous domain of 19 Gly-X-Y repeats and a motif conserved in the tumor necrosis factor (TNF)-related ligand family (see 604052). They found that ectodysplasin is a trimeric type II membrane protein that colocalizes with cytoskeletal structures at the lateral and apical surfaces of cells. These findings suggested that ectodysplasin is a novel member of the TNF-related ligand family involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.
Yan et al. (2000) found that the EDA-A1 isoform encodes a 391-residue protein with a domain similar to TNF at the C terminus. EDA-A1 specifically binds 'downless,' also known as EDAR (604095). An alternate transcript of EDA encodes a protein that is identical to EDA-A1 except for the deletion of 2 amino acids, glu308 and val309. This isoform is designated EDA-A2, and Yan et al. (2000) found that it exclusively binds to XEDAR (300276), an X-linked ectodysplasin receptor. EDA-A2 expression was concentrated in the central core of developing hair follicles in mice, whereas EDA-A1 expression was circumferential. Expression of EDA-A1 bound to EDAR was found at embryonic day 14 in the basal cells of developing epidermis, with elevated focal expression in placodes. Expression of EDA-A2 bound to XEDAR was barely discernible at this stage; however, by embryonic days 16 and 17, both receptors were expressed in large amounts in the maturing follicles. By postnatal day 1, the pattern of expression was confined to the hair follicles.
Chen et al. (2001) demonstrated that XHED is one of the few examples of a heritable disorder associated with failure of furin (136950) processing sites. The stalk region in the C terminus of the EDA molecule contains the sequence -arg-val-arg-arg156-asn-lys-arg159-, representing overlapping consensus cleavage sites (arg-X-lys/arg-arg) for the proprotein convertase furin. Missense mutations in 4 of the 5 basic residues within this sequence account for approximately 20% of all known XHED cases, with mutations occurring most frequently at arg156, which is shared by the 2 consensus furin sites. See 300451.0005, 300451.0006, and 300451.0007. The analyses of Chen et al. (2001) suggested that cleavage at the furin site(s) in the stalk region is required for the ectodysplasin-mediated cell-to-cell signaling that regulates the morphogenesis of ectodermal appendages. They showed that the 50-kD EDA parent molecule is cleaved at -arg156-asn-lys-arg159- to release the soluble C-terminal fragment containing the TNF core domain. This cleavage appeared to be catalyzed by furin, as release of the TNF domain was blocked either by expression of the furin inhibitor or by expression of EDA in furin-deficient cells. Thus, mutation of a functional furin cleavage site in the developmental signaling molecule is a basis for XHED and raises the possibility that furin cleavage may regulate the ability of EDA to act as a juxtacrine or paracrine factor.
Elomaa et al. (2001) confirmed the findings of Chen et al. (2001). They further demonstrated that EDAR coprecipitated with ectodysplasin, confirming that they form a ligand-receptor pair. In situ hybridization and immunostaining studies showed that ectodysplasin and EDAR are expressed in adjacent or partially overlapping layers in the developing human skin. The authors concluded that as a soluble ligand ectodysplasin can interact with EDAR and mediate signals needed for the development of ectodermal appendages.
To elucidate the function of ED1 in pathways regulating ectodermal development, Durmowicz et al. (2002) analyzed promoter elements of the ED1 gene, which they called EDA. Using electrophoretic mobility shift assays and cotransfection studies, Durmowicz et al. (2002) demonstrated that lymphoid enhancer-binding factor-1 (LEF1; 153245) specifically binds the ED1 promoter, and that LEF1 and beta-catenin (116806) are necessary for full activation of ED1 gene expression. Also, inhibition of glycogen synthase kinase-3B (GSK3B; 605004), which stabilizes excess beta-catenin, stimulates transcription from the ED1 promoter. Durmowicz et al. (2002) concluded that the ED1 gene is a target of Wnt signaling. Using transfection experiments, they found no evidence for feedback signaling of ED1 on Lef1 and beta-catenin.
EDA-A1 and EDA-A2, the most common and longest EDA splice isoforms, activate NF-kappa-B-promoted transcription by binding to distinct receptors: EDAR and XEDAR. The extent to which any particular isoform is sufficient for the formation of hair, sweat glands, or teeth had been unclear. Srivastava et al. (2001) reported that transgenic expression of the mouse EDA-A1 isoform in Tabby males rescued development of several skin appendages. The transgenic Tabby mice showed almost complete restoration of hair growth, dermal ridges, sweat glands, and molars. The number of hair follicles in the transgenic mice is the same as in wildtype, although the development of follicles and associated glands varies from indistinguishable from wildtype to smaller and/or only partially formed. These results suggested that the other EDA isoforms may not be absolutely required for skin appendage formation but, consistent with distinctive temporal and spatial expression of the EDA-A2 isoform, are likely required for appropriate timing and completeness of development. These data provided direct physiologic evidence that EDA-A1 is a key regulator of hair follicle and sweat gland initiation; its soluble ligand form could aid in deriving therapeutic reagents for conditions affecting hair and sweat gland formation.
To analyze EDA pathways, Cui et al. (2002) used expression profiling on 15,000-gene mouse cDNA microarrays, comparing adult mouse skin from wildtype, EDA-defective (Tabby) mice, and Tabby mice supplemented with the EDA-A1 isoform, which is sufficient to rescue multiple Tabby phenotypes. Given the sensitivity of the microarray system, 8,500 genes (60%) were estimated to be expressed, including transcription factors and growth-regulatory genes that had not previously been identified in skin; however, only 24 (0.16%), one-third of them novel, showed significant differences between wildtype and Tabby. An additional 8 genes not included in the 15,000-gene set were shown to have expression differences by real-time RT-PCR. Sixteen of 32 affected genes were restored significantly toward wildtype levels in EDA-A1 transgenic Tabby mice. Significant upregulation in Tabby skin was observed for several dermal matrix genes, including Col1a1 (120150), Col1a2 (120160), Col3a1 (120180), and Sparc (182120). In contrast, downregulation occurred for the NEMO (300248)/NF-kappa-B (164011) pathway, already implicated in skin appendage formation, and even more markedly for a second pathway, JNK (601158)/c-jun (165160)/c-fos (164810) and their target genes, that had not previously been clearly associated with skin development. The authors concluded that EDA has a regulatory role in both the NF-kappa-B and JNK pathways.
Cui et al. (2003) conditionally expressed ED1 isoforms as tetracycline-regulated transgenes in Tabby and wildtype mice. Expression of only the EDA-A1 transgene had determinative effects on sweat glands and hair follicles, as well as trophic effects on sebaceous and Meibomian glands. The phenotypic effects of EDA-A1 on sebaceous glands, but not on hair follicles, were reversed when the gene was repressed in adult animals. Cui et al. (2003) proposed both initiating and trophic isoform-specific effects of the EDA gene, and suggested a possible balance of isoform interactions in skin appendage formation.
The EDA1 protein, acting through EDAR, is essential for proper formation of skin appendages. EDA1 must be proteolytically processed to a soluble form to be active. Gaide and Schneider (2003) showed that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescued the Tabby phenotype in the offspring. Notably, sweat glands can also be induced by EDA1 after birth. This was said to be the first example of a developmental genetic defect that can be permanently corrected by short-term treatment with the recombinant protein.
By comparative transcription profiling of embryonic skin during hair follicle development in wildtype and Tabby mice, Cui et al. (2006) found Eda regulated proteins involved in 4 signaling pathways. These included Shh (600725) in the hedgehog signaling pathway, Dkk4, (605417) in the Wnt signaling pathway, Sostdc1 (609675) in the BMP pathway, and Ltb (600978) in the NFKB (see 164011) signaling pathway. Ltb was enriched in developing hair follicles of wildtype but not Tabby mice. In mice lacking Ltb, all 3 types of mouse hairs were formed, but they were structurally abnormal. Cui et al. (2006) concluded that Ltb regulates the form of hair in developing hair follicles and failure of Ltb activation can account for part of the Tabby phenotype.
Kunisada et al. (2009) compared Tabby mice, in which sweat glands are not formed, with wildtype mice. Consistent with a controlled morphologic progression, expression profiling revealed stage-specific gene expression changes. Similar to the development of hair follicles, which are the other major skin appendage controlled by EDA, sweat gland induction and initial progression were accompanied by Eda-dependent upregulation of the Shh pathway. During the further development of sweat gland secretory portions, Foxa1 (602294) and Foxi1 (601093), which are not at all expressed in hair follicles, were progressively upregulated in wildtype but not in Tabby footpads. Upon completion of wildtype development, Shh declined to low levels seen in Tabby mice, but Fox family genes remained at elevated levels in mature sweat glands.
Harjunmaa et al. (2012) reported that mouse tooth complexity can be increased substantially by adjusting multiple signaling pathways simultaneously. Harjunmaa et al. (2012) cultured teeth in vitro and adjusted ectodysplasin (EDA), activin A (see 147290), and SHH pathways, all of which are individually required for normal tooth development. The authors quantified tooth complexity using the number of cusps and a topographic measure of surface complexity, and found that whereas activation of EDA and activin A signaling and inhibition of SHH signaling individually cause subtle to moderate increases in complexity, cusp number is doubled when all 3 pathways are adjusted in unison. Furthermore, the increase in cusp number does not result from an increase in tooth size, but from an altered primary patterning phase of development. The combination of a lack of complex mutants, the paucity of natural variants with complex phenotypes, and their results of greatly increased dental complexity using multiple pathways, suggests that an increase may be inherently different from a decrease in phenotypic complexity.
Kangas et al. (2004) reported that developmentally most dental characters may be nonindependent. The authors investigated how 3 different levels of the cell signaling protein ectodysplasin (Eda) changed dental characters in mouse. They found that with increasing expression levels of Eda, the number of cusps increased, cusp shapes and positions changed, longitudinal crests formed, and number of teeth increased. The consistent modification of characters related to lateral placement of cusps could be traced to a small difference in the formation of an early signaling center at the onset of tooth crown formation. Kangas et al. (2004) concluded that most aspects of tooth shape have the developmental potential for correlated changes during evolution which may, if not taken into account, obscure phylogenetic history.
Hypohidrotic Ectodermal Dysplasia 1, X-Linked
Kere et al. (1996) found that the EDA1 gene was disrupted in 6 hypohidrotic ectodermal dysplasia (XHED, ECTD1; 305100) patients with X/autosome translocations or submicroscopic deletions; 9 patients had point mutations (see, e.g., 300451.0001). The authors noted that mutations were detected in only one-tenth of the patients studied.
In 162 affected males and 21 females who were either obligate carriers or had manifestations of EDA, Ferguson et al. (1998) screened the 2 known exons of the ED1 gene. Approximately 7% of patients, all males, had putative mutations identified within exon 1 (see, e.g., 300451.0003), but no variants were found within exon 2. No correlation between phenotype and genotype was evident between either affected subjects or subjects with or without detectable mutations. The authors concluded that the remainder of the patients were likely to have mutations in as yet unidentified exons of the EDA gene.
In 17 of 18 families with X-linked hypohidrotic ectodermal dysplasia, Monreal et al. (1998) identified mutations in the EDA1 gene, including 12 missense, 1 nonsense, and 4 deletion mutations (see, e.g., 300451.0005-300451.0010 and 300451.0023). The results suggested that EDA1 isoform II plays a critical role in tooth, hair, and sweat gland morphogenesis, whereas the biologic significance of isoform I remained unclear.
In 12 of 15 EDA patients, Bayes et al. (1998) identified mutations in the EDA1 gene. Three mutations removed either 2 or 4 of the Gly-X-Y repeats without interrupting the reading frame, thus suggesting a functional role for the collagenous domain. Kobielak et al. (2001) identified mutations in the EDA gene, 2 of which were novel. Despite a different character and localization of the mutations, no apparent correlation between phenotype and genotype was found. Using SSCA and direct sequencing, Vincent et al. (2001) screened 52 unrelated XHED patients (42 familial and 10 sporadic cases) for mutations in the entire coding sequence of the EDA gene. A total of 34 mutated alleles (65%) were detected, including 22 different mutations, 14 of which were novel. The missense mutations arg155 to cys (R155C; 300451.0005), arg156 to cys (R156C; 300451.0006), and arg156 to his (R156H; 300451.0007), affecting CpG dinucleotides in exon 3, represented 35% of the mutated alleles. Review of the clinical features showed no obvious genotype/phenotype correlation. An inter- and intrafamilial variability of clinical expression in male patients was noticed. The X-inactivation pattern in leukocytes demonstrated a weak (if any) correlation with the severity of the disease in female carriers. Only 2 proven female carriers (8%) among the 26 examined showed no clinical sign. Combined with previous mutation reports, the authors tabulated a total of 56 different mutations (48 point mutations, including small deletions and insertions, and 8 larger deletions) reported in 85 independent patients. Mutations were distributed in all but exons 2 and 4. Whereas mutations in exons 3 and 8 are missense mutations, most of the mutations in exon 5 are deletions or insertions, probably due to the repetitive nature of this region favoring polymerase slippage.
Visinoni et al. (2003) tabulated 64 different mutations in the EDA gene that had been related to X-linked ectodermal dysplasia.
In affected members of a Han Chinese family with X-linked hypohidrotic ectodermal dysplasia, Huang et al. (2006) identified a de novo 1-bp insertion in exon 4 of the EDA gene (300451.0016). The authors stated that this was the first de novo insertion identified in the EDA gene.
Lexner et al. (2008) identified 16 different mutations in the EDA gene in 19 Dutch families with X-linked HED. Nine of the mutations were novel. In addition, multiplex ligation-dependent probe amplification (MLPA) analysis detected a deletion in exon 1. There were no genotype/phenotype correlations.
Ferrier et al. (2009) reported father-to-son transmission of XHED by sex chromosome heterodisomy (300451.0019).
In a Pakistani man with severe generalized hyperkeratosis who was originally diagnosed with Lelis syndrome (608290), van Steensel and van der Hout (2009) analyzed the EDA gene and identified the R156H (300451.0007) mutation. The authors suggested that Lelis syndrome may be a manifestation of X-linked HED.
Schneider et al. (2018) administered a recombinant fusion protein, Fc-EDA, consisting of the receptor-binding domain of EDA and the Fc domain of human IgG1, intraamniotically to an affected pair of twin male fetuses and an unrelated male fetus. The infants were able to sweat normally and XLHED-related illness had not developed by 14 to 22 months of age.
X-Linked Hypodontia
Tao et al. (2006) identified a mutation in the EDA gene (300451.0014) in affected members of a Mongolian family with selective tooth agenesis (STHAGX1; 313500). Tarpey et al. (2007) identified a mutation in the EDA gene (300451.0015) in an Indian family with X-linked hypodontia affecting the incisors.
In 4 affected males and 1 affected female carrier from a Chinese family with congenital hypodontia, Han et al. (2008) identified a mutation in the EDA gene (T338M; 300451.0018).
In 15 unrelated Chinese men with selective tooth agenesis, Song et al. (2009) sequenced the EDA gene and identified 4 patients with missense mutations: A259E (300451.0020) in 2 of the patients, and R289C (300451.0021) and R334H (300451.0022) in 1 each. None of the mutations were found in 60 Chinese female controls.
Shen et al. (2016) analyzed 6 mutations in the EDA gene, including the nonsyndromic tooth agenesis (STHAGX1)-associated variants A259E, R289C, R334H, and S374R, and 2 XHED-associated changes, H252L (300451.0023) and Y343C. The binding of all 4 STHAGX1-associated EDA proteins to the receptor EDAR was variably reduced compared to wildtype, whereas the 2 XHED-associated proteins showed complete loss of receptor-binding capability. Binding to the ectodysplasin A2 receptor (XEDAR) was also variably reduced with the tooth agenesis-associated proteins, and both XHED-causing mutants retained residual binding to XEDAR. Nuclear translocation of the NFKB subunit p65 (RELA; 164014) in the epithelium-derived ameloblast cell line LS8 was significantly reduced with all 6 EDA mutants compared to wildtype, and it was significantly more decreased in the XHED-causing mutants than in those associated with nonsyndromic tooth agenesis. Dual luciferase assay confirmed the impairment of transcriptional activation of NFKB by all 6 mutant proteins compared to wildtype EDA, with no significant difference observed between the STHAGX1- or XHED-associated mutants. RT-PCR analysis in transfected LS8 cells demonstrated significantly increased expression of BMP4 (112262) with the mutants compared to wildtype, and BMP4 expression was significantly more increased with the XHED-associated mutations than with the STHAGX1-associated mutations. In contrast, WNT10A (606268) expression was significantly downregulated by all 6 EDA mutants compared to wildtype EDA, and WNT10B (601906) expression was significantly downregulated by the XHED-associated mutants. Shen et al. (2016) suggested that EDA mutations associated with nonsyndromic tooth agenesis attenuate signaling through the NFKB pathway rather than completely blocking it, as occurs in XHED.
Casal et al. (2007) studied a canine model of XHED. Dogs have dentition similar to that in humans with respect to development and morphology of teeth. Also, clinical signs in humans and dogs with XHED are virtually identical, whereas several are missing in the murine equivalent. Casal et al. (2007) found that in the dog model the genetically missing EDA was compensated for by postnatal intravenous administration of soluble recombinant EDA. Untreated XHED dogs had an incomplete set of conically shaped teeth similar to those seen in human patients with XHED. After treatment with EDA, significant normalization of adult teeth was achieved in 4 of 5 XHED dogs. Moreover, treatment restored normal lacrimation and resistance to eye and airway infections and improved sweating ability. The results not only provided proof of concept for a potential treatment of this disorder but also demonstrated an essential role of EDA in the development of secondary dentition.
In a family with X-linked hypohidrotic ectodermal dysplasia (XHED, ECTD1; 305100) from the United Kingdom, Kere et al. (1996) identified a tyr61-to-his mutation in a novel transmembrane protein resulting from a T-to-C transition at nucleotide 423. This was 1 of 9 point mutations identified in patients with this disorder.
In a family with X-linked hypohidrotic ectodermal dysplasia (XHED, ECTD1; 305100) from the United Kingdom and another from the U.S., Kere et al. (1996) found an association between EDA and a point mutation, a G-to-T transversion at nucleotide 448 resulting in an arg69-to-leu amino acid substitution.
One of the relatively few EDA (305100) mutations found by Ferguson et al. (1998) in patients with XHED was a 366C-T transition resulting in a gln23-to-ter nonsense mutation.
One of the relatively few EDA (305100) mutations found by Ferguson et al. (1998) in patients with XHED was a 429G-A transition resulting in a glu63-to-lys amino acid substitution.
In a patient with XHED (305100), Monreal et al. (1998) found a 704C-T transition in exon 3 of the EDA gene, causing an arg155-to-cys amino acid substitution in isoform II of the EDA protein.
In a patient with XHED (305100), Monreal et al. (1998) found a 707C-T transition in exon 3 of the EDA gene, predicted to result in an arg156-to-cys amino acid substitution in isoform II of the EDA protein. This was a de novo mutation.
In a patient with XHED (305100), Monreal et al. (1998) found a 708G-A transition in exon 3 of the EDA gene, resulting in an arg156-to-his amino acid substitution in isoform II of the EDA protein.
In a study of 52 unrelated patients with XHED, Vincent et al. (2001) detected the R156H mutation in 9 patients. Haplotype analysis using markers closely flanking the EDA gene and 2 intragenic polymorphisms demonstrated that R156H, R155C (300451.0005), and R156C (300451.0006) arose independently. The mutation appeared de novo in 3 of the cases.
In a Pakistani man with severe generalized hyperkeratosis who was originally diagnosed with Lelis syndrome (608290), van Steensel and van der Hout (2009) analyzed the EDA gene and identified the R156H mutation. The authors suggested that Lelis syndrome may be a manifestation of X-linked HED.
In a patient with XHED (305100), Monreal et al. (1998) found an 867C-T transition in exon 5, predicted to result in a pro209-to-leu amino acid substitution in isoform II of the EDA protein.
In a patient with XHED (305100), Monreal et al. (1998) found a 912G-C transversion in exon 5 of the EDA gene, predicted to result in a gly224-to-ala amino acid substitution in isoform II of the EDA protein.
In 2 apparently unrelated families, Monreal et al. (1998) found that males with XHED (305100) had a 1285G-A transition in exon 9 of the EDA gene, predicted to result in an ala349-to-thr amino acid substitution in isoform II of the EDA protein. Since in 1 of these families the affected male represented a de novo mutation, the 2 families were almost certainly not related.
In a Japanese patient with EDA (305100), Yotsumoto et al. (1998) found a change of codon 61 from TAC (tyr) to TAG (stop). This nonsense mutation (tyr61 to ter) occurred in the same codon, located on the most extracellular end of the transmembrane domain, as that involved in the relatively frequent Y61H missense mutation (300451.0001).
In 1 of 4 Brazilian families with XHED (305100), Visinoni et al. (2003) described a 36-bp deletion in exon 5 responsible for the loss of 4 Gly-X-Y repeats of the collagen subdomain of ectodysplasin A. The deletion had already been reported in 8 other families. Seven different breakpoints can lead to the same deletion result. The mutational process leading to the deletion may vary in the reported families. The experience indicates the importance of the Gly-X-Y repeats of the collagen subdomain in the function of ectodysplasin A (Bayes et al., 1998).
In 1 of 4 Brazilian families with XHED (305100), Visinoni et al. (2003) described a guanine deletion at exon 6 of the EDA gene (either 966 or 967 site) that altered ectodysplasin A after amino acid 241 and led to a premature ending at amino acid 279.
In a Mongolian family segregating X-linked isolated congenital hypodontia (STHAGX1; 313500), Tao et al. (2006) identified a 193C-G transversion in exon 1 of the EDA gene, resulting in an arg65-to-gly (R65G) substitution in the juxtamembrane region of the protein, in all affected males and carrier females. The mutation was not found in 90 unrelated normal Han Chinese individuals.
In affected individuals from a large Indian family with X-linked hypodontia (STHAGX1; 313500), Tarpey et al. (2007) identified a 1072C-G transversion in exon 8 of the EDA gene, resulting in a gln358-to-glu (Q358E) substitution. The residue is completely conserved in all species observed, but is predicted to only partially disrupt protein function, consistent with the unique hypodontia phenotype. Most patients had absence of all mandibular incisors and maxillary lateral incisors with maxillary central incisors missing in some cases. Both primary and permanent dentition were affected.
In 2 Han Chinese brothers with X-linked hypohidrotic ectodermal dysplasia (305100) and their unaffected mother, Huang et al. (2006) identified a 1-bp insertion (573insT) in exon 4 of the EDA gene. The mutation was not found in the maternal grandparents or in 200 controls. The authors stated that this was the first de novo insertion identified in the EDA gene.
In a boy with X-linked hypohidrotic ectodermal dysplasia (305100), Schneider and Muhle (2009) identified 2-bp insertion (913insTA) in exon 8 of the EDA gene, resulting in a frameshift and premature termination. His unaffected mother was heterozygous for the mutation. Sequence analysis indicated that the insertion represented a TA repeat expansion that was likely susceptible to slipped-strand mispairing during DNA replication.
In 4 affected males from a Chinese family with congenital hypodontia (STHAGX1; 313500), Han et al. (2008) identified a hemizygous 1013C-T transition in exon 8 of the EDA gene, resulting in a thr338-to-met (T338M) substitution that changes the residue from hydrophilic to hydrophobic and is predicted to cause a conformational change affecting the stability of the homotrimer. The mutation was found in 6 female carriers, including 1 affected female with missing lateral incisors, but not in unaffected family members, and was not found in 120 control chromosomes.
In a boy and his affected father with X-linked hypohidrotic ectodermal dysplasia (XHED; 305100), Ferrier et al. (2009) detected hemizygosity for an 826C-T transition in exon 7, resulting in an arg276-to-cys (R276C) substitution. Results of analysis of polymorphic X chromosome markers were consistent with paternal inheritance of the X chromosome. Family history revealed an affected paternal great-great uncle, a male first cousin once removed, and 2 male second cousins. Analysis of the EDA gene in the 2 second cousins showed hemizygosity for the R276 mutation, which was inherited from their carrier mother.
In 2 unrelated Chinese men with selective tooth agenesis (STHAGX1; 313500), Song et al. (2009) identified a c.776C-A transversion in exon 6 of the EDA gene, resulting in an ala259-to-glu (A259E) substitution at a residue on the outer surface of the homotrimer. The mutation was shown to have arisen de novo in 1 of the patients, and was not found in 60 Chinese female controls.
In a Chinese man with selective tooth agenesis (STHAGX1; 313500), Song et al. (2009) identified a c.865C-T transition in exon 7 of the EDA gene, resulting in an arg289-to-cys (R289C) substitution at a residue on the outer surface of the homotrimer. His unaffected mother carried the mutation, which was not found in 60 Chinese female controls.
In a Chinese man with selective tooth agenesis (STHAGX1; 313500), Song et al. (2009) identified a c.1001G-A transition in exon 8 of the EDA gene, resulting in an arg334-to-his (R334H) substitution at the monomer-monomer interface. His unaffected mother carried the mutation, which was not found in 60 Chinese female controls.
In a patient with X-linked hypohidrotic ectodermal dysplasia (XHED; 305100), Monreal et al. (1998) identified heterozygosity for a 986A-T transversion in exon 7 of the EDA gene, resulting in a his252-to-leu (H252L) substitution in isoform II of the EDA protein. The mutation was not found in 60 control X chromosomes.
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