Disease relevance of EDAR

• Genetic subtypes of HIV-1 were determined using the heteroduplex mobility assay (HMA) using ED5/ED12 as outer and ES7/ES8 as inner primers [1].
• Hypothetically, the deletion extends beyond the 5' end and probably includes a second contiguous gene responsible for leiomyomatosis (the DL gene) and even a third one coding for congenital cataract (the CCT gene) [2].
• Treatment with 5-aza-2'-deoxycytidine restored XEDAR expression in breast cancer cell lines with methylated XEDAR promoter and sensitized them to EDA-A2-induced cell death [3].

High impact information on EDAR

• We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling [4].
• This insertion functions to determine receptor binding specificity, such that EDA-A1 binds only the receptor EDAR, whereas EDA-A2 binds only the related, but distinct, X-linked ectodysplasin-A2 receptor (XEDAR) [5].
• Thus, cells born by embryonic day 5 (ED-5) give rise predominantly to photoreceptors when isolated for culture on ED-6 but develop mainly as neurons when isolated on ED-8 [6].
• A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13 [7].
• Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03 [7].

Biological context of EDAR

• During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation [8].
• We present evidence that EDAR is capable of activating the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways and that these activities are impaired in mutants lacking its death domain or those associated with anhidrotic ectodermal dysplasia and the downless phenotype [9].
• Collectively, the above results suggest that EDAR utilizes a novel signal transduction pathway [9].
• 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 [10].
• 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 [11].

Anatomical context of EDAR

• Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth [12].
• Dysfunction of Edar signalling causes hypohidrotic/anhidrotic ectodermal dysplasia (ED), a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth [13].
• In addition there were small numbers of cells expressing novel markers such as markers usually found only on macrophage subsets in splenic tissue (ED3) and a recently described marker for veiled dendritic cells (OX62) [14].
• Thus, our data demonstrate that in addition to its well-established role in HF morphogenesis, Edar signaling is also involved in hair cycle control and regulates apoptosis in HF keratinocytes during catagen [15].
• By ED5, the virus had spread extensively within the limb and the adjacent somites with little rostral or caudal expansion of the infection along the axial midline [16].

Associations of EDAR with chemical compounds

• This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X), thereby truncating the protein [17].
• Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively) [18].
• It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway [18].
• The teeth were restored with either Clearfil Liner Bond II (LB II), One-Step (OS), or Super-Bond D Liner (DL), followed by Clearfil Photo Posterior resin composite [19].
• Compared to controls, the magnitude of the Ca2+ transient in the presence of nifedipine was reduced by 41% at ED5, 77% at ED11, and 78% at ED15 [20].

Physical interactions of EDAR

• Finally, ectodysplasin A can physically interact with the extracellular domain of EDAR and thus represents its biological ligand [9].

Other interactions of EDAR

• Although EDAR possesses a death domain, it did not interact with the death domain-containing adaptor proteins TRADD and FADD [9].
• Using expression studies in tissue culture cells, we found that the R375H substitution in EDAR caused loss of its affinity for EDARADD and reduced activation of the downstream target NF-kappaB [21].
• To gain further insight into the mechanism of IKK activation by Edar and Edaradd, we performed a yeast two-hybrid screen and isolated TAB2 (TAK1-binding protein 2) as a binding partner of Edaradd [13].

Analytical, diagnostic and therapeutic context of EDAR

• In situ hybridization and immunostaining studies show that ectodysplasin and EDAR are expressed in adjacent or partially overlapping layers in the developing human skin [22].
• 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 [23].
• Catagen development accompanied by increased apoptosis in the outer root sheath was significantly accelerated in downless mice or after treatment of wild-type mice by a fusion protein that inhibits Edar signaling, compared with the corresponding controls [15].
• MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes [18].
• Fluorescence-activated cell sorting indicated that essentially all of the DL-staining cells were nonviable [24].

References