Definitive Evidence for an Autosomal Recessive Form of Hypohidrotic Ectodermal Dysplasia Clinically Indistinguishable rom the More Common X-Linked Disorde

Munoz, Felix; Lestringant, Gilles G.; Sybert, Virginia P.; Frydman, Moshe; Alswaini, A.; Frossard, Philippe; Jorgenson, Ronald J.; Zonana, Jonathan

doi:10.1086/513905

Cited by 67 publications

(46 citation statements)

References 18 publications

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“…The recent discovery of mutations in EDA and EDAR in families with X-linked and autosomal forms of hypohidrotic ectodermal dysplasias has led to an increased appreciation of the role of this family in the regulation of embryonic development and epithelial morphogenesis (2,14,27,28). XE-DAR is a recently isolated homolog of EDAR and, like it, is highly expressed in the ectoderm during embryonic development (7).…”

Section: Discussionmentioning

confidence: 99%

Role of TRAF3 and -6 in the Activation of the NF-κB and JNK Pathways by X-linked Ectodermal Dysplasia Receptor

Sinha

Zachariah

Quiñones

et al. 2002

Journal of Biological Chemistry

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X-linked ectodermal dysplasia receptor (XEDAR) is a recently isolated member of the tumor necrosis factor receptor family that has been shown to be highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2). By using a subclone of 293F cells with stable expression of XEDAR, we report that XEDAR activates the NF-B and JNK pathways in an EDA-A2-dependent fashion. Treatment with EDA-A2 leads to the recruitment of TRAF3 and -6 to the aggregated XEDAR complex, suggesting a central role of these adaptors in the proximal aspect of XEDAR signaling. Whereas TRAF3 and -6, IKK1/IKK␣, IKK2/IKK␤, and NEMO/IKK␥ are involved in XEDARinduced NF-B activation, XEDAR-induced JNK activation seems to be mediated via a pathway dependent on TRAF3, TRAF6, and ASK1. Deletion and point mutagenesis studies delineate two distinct regions in the cytoplasmic domain of XEDAR, which are involved in binding to TRAF3 and -6, respectively, and play a major role in the activation of the NF-B and JNK pathways. Taken together, our results establish a major role of TRAF3 and -6 in XEDAR signaling and in the process of ectodermal differentiation.

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Section: Discussionmentioning

confidence: 99%

Role of TRAF3 and -6 in the Activation of the NF-κB and JNK Pathways by X-linked Ectodermal Dysplasia Receptor

Sinha

Zachariah

Quiñones

et al. 2002

Journal of Biological Chemistry

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“…Polymorphic markers DXS1689, DXS1690 and DXS339 closely flanking the ED1 gene 8,12 and two intragenic polymorphisms (IVS4+27T4A and IVS5+8delCC) were used in order to define haplotypes in patients from different extraction bearing identical mutations.…”

Section: Microsatellite Genotypingmentioning

confidence: 99%

“…5,6 Inter-and intrafamilial variability of clinical expression in male patients was noticed in our series as in a previous report. 25 XLHED shows partial penetrance in female carriers 12,26,27 and the probability to detect them by clinical examination was estimated as being 60 ± 70%. 28 This should be reappraised with regard to the contribution of molecular analysis.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

“…3,10,11 So mutation analysis enables diagnosis in sporadic cases and carrier detection in female relatives avoiding the difficulties of genetic counselling due to the rarer, autosomal form of the disorder (AHED), which is clinically indistinguishable from XLHED, in affected males. 1,3,5,12,13 The ED1 gene undergoes extensive alternative splicing. This generates several transcripts: the initially described shortest EDA-O form (two exons encoding a 135 aminoacid protein, mutated in 5 ± 10% of XLHED patients), the longest EDA-A form (nine exons, 391 aminoacids) and five others forms.…”

Section: Introductionmentioning

confidence: 99%

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Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia

et al. 2001

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X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of the ectodermal dysplasias characterised by an abnormal development of eccrine sweat glands, hair and teeth. The ED1 gene responsible for the disorder undergoes extensive alternative splicing and to date few studies have concerned the full length transcript. We screened 52 unrelated families or sporadic cases for mutation in the full coding sequence of this gene. SSCA analysis or direct sequencing allowed identification of mutations in 34 families: one initiation defect, twenty-two missenses, two nonsense, eight insertions or deletions, and a large deletion encompassing all the ED1 gene. Fourteen of these mutations have not been previously described, including five missenses. One third of identified mutations were localised in codons 155 and 156, affecting CpG dinucleotides and nine of them correspond to the R156H missense. Hypothesis of a founder effect has been ruled out by haplotype analysis of flanking microsatellites. These recurrent mutations indicate the functional importance of the positively charged domain of the protein. Including our data, there are now 56 different mutations reported in 85 independent patients, that we have tabulated. Review of clinical features in the present series of affected males and female carriers showed no obvious correlation between the type of mutations, the phenotype and its severity. The X-chromosome pattern of inactivation in leucocytes showed little correlation with expressivity of the disease in female carriers. Finally this study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ED1 gene.

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“…After the initial diagnosis, the pattern of inheritance should be determined, since X-linked hemizygous males and autosomal recessive forms are not phenotypically distinguishable [19]. One of the main tasks in the case of a patient with HED is to find other possible carriers of the disorder in the patient's family and to analyze the pattern of inheritance [18].…”

Section: Discussionmentioning

confidence: 99%

Orofacial Features of Hypohidrotic Ectodermal Dysplasia

Aquino

Paranaíba

Swerts

et al. 2012

Head and Neck Pathol

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Hypohidrotic ectodermal dysplasia (HED) is a type of genodermatosis characterized by the abnormal development of sweat glands, teeth, and hair. The most prevalent form of HED is X-linked hypohidrotic ectodermal dysplasia (XLHED), which is associated with mutations in the EDA gene. The aim of this case report was to describe a family with XLHED with emphasis on differences in orofacial features between members. Family members were systematically evaluated to characterize the pattern of inheritance and clinical features. Dental examination included evaluation of agenesis and abnormal teeth structure. The pedigree of the last seven generations of the family was constructed. Clinical examination and medical history revealed five males affected by HED and nine female as heterozygous carriers. The males exhibited the classic phenotype of XLHED, with dental abnormalities, hypohydrosis, and craniofacial dysmorphologies. The heterozygous carriers of the X-linked gene defect principally exhibited dental agenesis of the lateral maxillary incisors. Careful clinical examination, including dental evaluation, is an important way to detect heterozygous carriers of X-linked HED. Heterozygous parents of patients with HED may also show some features of the disorder. The identification of female carriers results in genetic counseling being offered to affected families, as well as providing adequate treatment as necessary and long-term follow-up of these patients.

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Definitive Evidence for an Autosomal Recessive Form of Hypohidrotic Ectodermal Dysplasia Clinically Indistinguishable rom the More Common X-Linked Disorde

Cited by 67 publications

References 18 publications

Role of TRAF3 and -6 in the Activation of the NF-κB and JNK Pathways by X-linked Ectodermal Dysplasia Receptor

Role of TRAF3 and -6 in the Activation of the NF-κB and JNK Pathways by X-linked Ectodermal Dysplasia Receptor

Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia

Orofacial Features of Hypohidrotic Ectodermal Dysplasia

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