Disease relevance of EDA

• We have used the baculovirus/insect cell system to express the recombinant EDA proteins fused to the Fc portion of a truncated human IgG1 immunoglobulin heavy chain [1].
• X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a genetic disorder characterized by absence or deficient function of hair, teeth and sweat glands [2].
• NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) [3].
• Anhidrotic ectodermal dysplasia (ED1) is characterized by hypotrichosis, reduced number of sweat glands, and incisior anodontia in human, mouse, and cattle [4].
• In mice, lack of Eda leads to failure in primary hair placode formation and missing or abnormally shaped teeth, whereas mice overexpressing Eda are characterized by enlarged hair placodes and supernumerary teeth and mammary glands [5].

Psychiatry related information on EDA

• We present a child with severe mental retardation, a central nervous system malformation, signs of ectodermal dysplasia, and a distinct craniofacial dysmorphism [6].
• This result indicates that the reaction time of the EDA-2 pathway of the left hemisphere was shorter than the right for right-handed subjects [7].
• Adaptive behavior of school-age children with hypohidrotic ectodermal dysplasia [8].

High impact information on EDA

• We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling [9].
• X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling [9].
• Mutations in GJB6 cause hidrotic ectodermal dysplasia [10].
• Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia [11].
• The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse [12].

Chemical compound and disease context of EDA

• Eight patients (77 joints) with polyarthritis were treated systemically with 570 MBq (15.4 mCi) of rhenium 186 ((186)Re) hydroxyethylidenediphosphonate (HEDP) [13].
• Rhenium-186 (tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that simultaneously localizes in multiple skeletal metastases in patients with advanced cancer [14].
• The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain [15].
• The activities of CDP reductase and thymidine kinase were reduced in patients with the hyperimmunoglobulin E syndrome, congenital cytomegalovirus infection, anhidrotic ectodermal dysplasia with hyperimmunoglobulin A, Bloom's syndrome, immunodeficiency with hyperimmunoglobulinemia, and Down's syndrome [16].
• A phase IV, open-label, multicenter survey of 983 obstetrician-gynecologists was conducted to evaluate the incidence of intermenstrual bleeding in 6,382 women receiving a low-dose monophasic oral contraceptive, ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) over a six-month period [17].

Biological context of EDA

• These analyses suggest that cleavage at the furin site(s) in the stalk region is required for the EDA-mediated cell-to-cell signaling that regulates the morphogenesis of ectodermal appendages [18].
• Some EDA patients have missense mutations affecting this recognition sequence, suggesting that cleavage has biological significance in vivo [19].
• In contrast to the diversity of genes underlying ectodermal dysplasia disease phenotypes in humans, none of these EDA pathway components map to chromosomes previously shown to modify armor plates in natural populations, though EDAR showed a small but significant effect on plate number [20].
• The purified EDA immunoadhesins were endowed with ligand-binding activity as they could bind EDAR or XEDAR on the surface of 293T cells that had been transiently transfected with the corresponding plasmids [1].
• Recent findings have elucidated the cause of the autosomal forms of EDA, both dominant and recessive, and indicated an important role of a signal transduction pathway involving a protein product of the NEMO gene and the transcription factor NFkappaB in the differentiation of skin appendages [21].

Anatomical context of EDA

• Mutations in EDA give rise to a clinical syndrome characterized by loss of hair, sweat glands, and teeth [22].
• Anhidrotic ectodermal dysplasia (EDA) is an X-linked disorder characterized by abnormal development of ectoderm and its appendices [19].
• Further ordering of the loci could be inferred from a human/rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion [23].
• Hair follicles expressed EDA mRNA from 18 weeks [24].
• Starting at Week 12, osteoblasts and thymus were positive for EDA mRNA [24].

Associations of EDA with chemical compounds

• Here we show that the 50-kDa EDA parent molecule is cleaved at -Arg156Asn-Lys-Arg(159 downward arrow)- to release the soluble C-terminal fragment containing the TNF core domain [18].
• Importantly, the key residue cysteine 417 at the zinc finger domain of IKKgamma has been found to be mutated to arginine (IKKgammaC417R) in a human genetic disorder called the anhydrotic ectodermal dysplasia with immunodeficiency [25].
• A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappaB activation [26].
• The concentration of the proscillaridin A immunoreactivity ED1 in normotensive subjects had a geometric mean of 0.1 nmol/L, with a dispersion factor of 8.77 [27].
• The EDA exon of the fibronectin gene is a typical example of an exon bearing a purine-rich exon splicing enhancer (ESE) element recognised by members of the SR phosphoprotein family [28].

Physical interactions of EDA

• Finally, ectodysplasin A can physically interact with the extracellular domain of EDAR and thus represents its biological ligand [29].
• The purified EDA protein was shown to bind to TLR4-expressing HEK293 cells and to activate the TLR4 signaling pathway [30].

Regulatory relationships of EDA

• In addition, indirect stabilization of endogenous beta-catenin stimulated EDA transcription 4- to 13-fold [31].

Other interactions of EDA

• Dysfunction of Edar signalling causes hypohidrotic/anhidrotic ectodermal dysplasia (ED), a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth [32].
• The stalk region of EDA contains the sequence -Arg-Val-Arg-Arg156-Asn-Lys-Arg159-, representing overlapping consensus cleavage sites (Arg-X-Lys/Arg-Arg( downward arrow)) for the proprotein convertase furin [18].
• X-linked hypohidrotic ectodermal dysplasia (XLHED) is a heritable disorder of the ED-1 gene disrupting the morphogenesis of ectodermal structures [18].
• Oligodontia, sparse hair and deficiency of eccrine sweat glands are the features characteristic for the phenotype of the patients with anhidrotic ectodermal dysplasia (EDA) [33].
• A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency [34].

Analytical, diagnostic and therapeutic context of EDA

• Sequence analysis of the EDAR gene identified two novel mutations in the families: a missense mutation (G382S) in family A and a 4-bp deletion (718delAAAG) in family B. CONCLUSIONS: We describe novel mutations in the EDAR gene in two Pakistani families affected with the autosomal recessive form of HED [35].
• To study the expression of the human gene defective in EDA in human fetal development (Weeks 6-23 of gestational age) and in adult tissues, in situ hybridization and immunohistochemistry were used [24].
• X-linked hypohidrotic ectodermal dysplasia: localization within the region Xq11-21.1 by linkage analysis and implications for carrier detection and prenatal diagnosis [36].
• Analysis using quantitative RT-PCR confirms that MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting that this chemoattractant may help drive mononuclear cell accumulation in the expanding intima [37].
• Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia was previously performed by the direct histological analysis of fetal skin obtained by late second trimester fetoscopy [38].

References