Alternative titles; symbols
HGNC Approved Gene Symbol: EDNRA
SNOMEDCT: 1216943004;
Cytogenetic location: 4q31.22-q31.23 Genomic coordinates (GRCh38): 4:147,481,097-147,544,954 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.22-q31.23 | {Migraine, resistance to} | 157300 | Autosomal dominant | 3 |
| Mandibulofacial dysostosis with alopecia | 616367 | Autosomal dominant | 3 |
The endothelin receptor with highest affinity for ET1 (131240) has been called ETA. Cyr et al. (1991) isolated a cDNA clone of a human endothelin receptor from a placental cDNA library. The deduced amino acid sequence was 94% identical to the bovine endothelin ETA receptor and was judged to represent the human homolog.
Hosoda et al. (1992) isolated and characterized the gene for the human endothelin-A receptor. Southern blot analyses demonstrated that it is present in single copy. Northern blot analyses demonstrated a 4.3-kb mRNA in a wide variety of human tissues with the highest level in the aorta and a substantial level in cultured human mesangial cells.
Hosoda et al. (1992) determined that the EDNRA gene spans more than 40 kb and contains 8 exons and 7 introns. The transcription start site, determined by primer extension experiments, was 502 bp upstream of the methionine initiation codon.
Cyr et al. (1991) assigned the ETRA gene to chromosome 4 by analysis of its segregation pattern in rodent/human hybrids. Using human/rodent somatic hybrid cell DNAs, Hosoda et al. (1992) also assigned the gene to chromosome 4.
To investigate the influence of pregnancy-specific hormonal environment on expression of ET1 and the ET1 receptor (EDNR), Bourgeois et al. (1997) cultured and characterized vascular smooth muscle cells from stem villi vessels. They investigated whether the muscular layer of stem villi vessels could be a site of the ET1 expression described in the placenta, and they examined this expression in placental vascular smooth muscle cells (PVSMCs). Peptide precursors prepro-ET1 and prepro-ET3 mRNAs were identified in stem villi vessels, whereas only prepro-ET1 mRNA was observed in PVSMCs. The authors characterized EDNR expressed by these cells in comparison with the muscular layer of stem villi vessels. Whereas both the A and B (131244) forms of EDNR are present in stem villi vessels, they found that PVSMCs exclusively express the A form of the receptor, EDNRA. They described an alternatively spliced EDNRA transcript that is generated by exclusion of exon 3 in stem villi vessels and PVSMCs. The authors concluded that alternative splicing mechanisms of EDNRA mRNA could constitute a control of the abundance of active EDNRA in terms of contractility.
Maggi et al. (2000) demonstrated that in FNC-B4 cells, which are derived from a human fetal olfactory epithelium, both sex steroids and odorants regulate GnRH secretion. They found biologic activity of EDN1 in this GnRH-secreting neuronal cell. In situ hybridization and immunohistochemistry revealed gene and protein expression of EDN1 and its converting enzyme (ECE1; 600423) in both fetal olfactory mucosa and FNC-B4 cells. Experiments with radiolabeled EDN1 and EDN3 (131242) strongly indicated the presence of 2 classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies using selective analogs indicated that these 2 classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion.
Endothelin-1 inhibits active Na-K transport by as much as 50% in the renal tubule and other tissues (Zeidel et al., 1989). Okafor and Delamere (2001) noted that the presence of low levels of ET1 in aqueous humor combined with the potential for release of ET1 from ciliary processes suggested that the crystalline lens could be exposed to ET1 in vivo. They studied the influence of ET1 on active Na-K transport in the porcine lens. Their results suggested that ET1 inhibited active lens Na-K transport by activating EDNRA and EDNRB. Activation of the ET receptors also caused an increase in cytoplasmic calcium concentration in cultured lens epithelial cells. Both responses to ET1 appear to have a tyrosine kinase step.
Maurer et al. (2004) showed that endothelin receptor type A-dependent mast cell activation can diminish both endothelin-1 levels and endothelin-1-induced pathology in vivo and also can contribute to optimal survival during acute bacterial peritonitis. The authors concluded that their findings identified a new biologic function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.
Campia et al. (2004) examined forearm blood flow responses to intraarterial injection of an endothelin-A receptor blocker in 37 normotensive and 27 hypertensive patients. In hypertensive patients, the vasodilator effect of the blocker was significantly higher in blacks than in whites (p = 0.01), whereas blood flow was not significantly affected in black or white healthy controls. Campia et al. (2004) concluded that hypertensive blacks have enhanced EDNRA-dependent vasoconstrictor tone, which they suggested might be related to increased production of ET1.
Makita et al. (2008) demonstrated in mouse embryos that the endothelium family member Edn3, acting through the endothelin receptor EdnrA, directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. Makita et al. (2008) concluded that their findings established a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and implicated endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, the findings suggested a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.
Using a mouse line in which lacZ was knocked-in to the Ednra locus, Gordon et al. (2015) observed strong expression of Ednra in hair follicles at multiple stages of follicular development. They also observed Ednra expression in developing eyelids and in pinnae, particularly the dorsal and ventral regions of the pinnae that fuse with the scalp in EDNRA-associated mandibulofacial dysostosis (see MOLECULAR GENETICS).
Mandibulofacial Dysostosis with Alopecia
In 4 unrelated patients with mandibulofacial dysostosis and alopecia (MFDA; 616367), Gordon et al. (2015) identified heterozygosity for 2 different de novo missense mutations in the EDNRA gene (Y129F, 131243.0002 and E303K, 131243.0003). In vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling.
Associations Pending Confirmation
For discussion of a possible association between migraine (see 157300) and variation in the EDNRA gene, see 131243.0001.
For discussion of a possible association between intracranial aneurysm and variation in the EDNRA gene, see 105800.
Yanagisawa et al. (1998) and Clouthier et al. (1998) showed that mice deficient in either EDNRA or ECE1 develop defects in a subset of cephalic and cardiac neural crest derivatives. Ednra-null mice show defects in craniofacial structures, great vessels, and cardiac outflow tract. Ece1-null mice exhibit a virtually identical phenotype to Ednra-deficient and endothelin-1-deficient embryos due to the absence of biologically active endothelin-1. Ece1-deficient mice lack enteric neurons and epidermal/choroidal melanocytes, reproducing the phenotype of Edn3 (131242) and Ednra knockout mice. Yanagisawa et al. (1998) elaborated on the role of the Edn1/Ednra pathway in the patterning of the aortic arch in mice.
Charite et al. (2001) stated that Hand2 (602407) is essential for craniofacial development in the mouse. They found that expression of a Hand2 reporter was completely absent in branchial arches 1 and 2 of Ednra -/- mouse embryos, although Hand2 expression in other areas, including heart, was unaffected. Charite et al. (2001) identified a conserved functional ATTA motif within the 5-prime UTR of the Hand2 upstream region that was bound by Dlx6 (600030), but not by Dlx5 (600028) or Dlx2 (126255), in an Ednra-dependent manner. In addition, Dlx6 expression was undetectable in the first branchial arch in Ednra -/- embryos, whereas Dlx6 expression in more proximal regions appeared independent of Ednra signaling. Charite et al. (2001) concluded that Dlx6, Hand2, and Ednra signaling is involved in a complex regulatory program for craniofacial development in the mouse.
Using Ednra -/- and Dlx5 -/- Dlx6 -/- mutant mouse embryos, Heude et al. (2010) found that Dlx5 and Dlx6 were required for masticatory muscle formation independent of Ednra or loss of mandibular identity.
In zebrafish with morpholino knockdown of both EDNRA orthologs (ednraa and ednrab), Gordon et al. (2015) observed complete absence or reduction in length of the Meckel cartilage of the jaw, but no other gross abnormalities. Coinjection of various ligand and mutant or wildtype receptor combinations resulted in a range of rostral hypoplasia phenotypes of variable penetrance.
Tzourio et al. (2001) tested the association between migraine (see 157300) and gene polymorphisms of the endothelin system in a population-based study of 1,188 elderly individuals in Nantes, France. Migraine was diagnosed in 140 participants (11.9%). The endothelin receptor type A -231 A/G polymorphism was the only polymorphism significantly associated with migraine. There was a trend of decreasing prevalence of migraine with number of copies of the G allele (AA genotype: 15.7% with migraine, AG: 9.7%, GG: 2.9%; p less than 0.001). Carrying the G allele was associated with a sex- and age-adjusted odds ratio of 0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was stronger in participants with than in those without a family history of severe headaches.
Miao et al. (2012) performed a metaanalysis of 3 studies of the relationship between the -231G-A polymorphism in EDNRA and migraine, including the report of Tzourio et al. (2001). The metaanalysis included 440 migraineurs, 222 subjects with tension-type headaches, and 1,323 controls. A significant difference was found between migraineurs and controls with AA genotype versus AG+GG, and pooled relative risk with fixed effect was 4.04 (95% CI 1.17-1.59; p = 0.000). There was no statistically significant difference between tension-type headaches and controls (p = 0.774).
In 3 unrelated patients with mandibulofacial dysostosis and alopecia (MFDA; 616367), including a boy who was originally reported by Zechi-Ceide et al. (2010), Gordon et al. (2015) identified heterozygosity for a de novo c.386A-T transversion (c.386A-T, NM_001957.3) in the EDNRA gene, resulting in a tyr129-to-phe (Y129F) substitution at a highly conserved residue. In 1 of the patients, somatic mosaicism for the mutation was confirmed; Gordon et al. (2015) noted that because a similar degree of mosaicism was observed in 2 tissue sources, the mutation was likely to have arisen within the first few divisions after conception. Gordon et al. (2015) also noted that the Y129F substitution had previously been shown to increase the affinity of EDNRA for the nonpreferred ligand, EDN3 (131242); in vitro and in vivo analysis indicated that the Y129F variant has the capacity to perturb EDNRA activity in an endothelin ligand-dependent manner.
In a girl with mandibulofacial dysostosis and alopecia (MFDA; 616367) who was originally described by Cushman et al. (2005), Gordon et al. (2015) identified heterozygosity for a de novo c.907G-A transition (c.907G-A, NM_001957.3) in the EDNRA gene, resulting in a glu303-to-lys (E303K) substitution at a highly conserved residue in the C-terminal portion of the third intracellular loop. Analysis of exome sequencing reads indicated a 75%:25% bias in reference- versus variant-containing reads in the patient; Sanger sequencing showed a similar bias in wildtype versus mutant chromatogram peak height, suggesting that the patient was somatic mosaic for E303K. In vitro and in vivo analysis indicated that the E303K variant has the capacity to perturb EDNRA activity in an endothelin ligand-dependent manner.
Bourgeois, C., Robert, B., Rebourcet, R., Mondon, F., Mignot, T.-M., Duc-Goiran, P., Ferre, F. Endothelin-1 and ET(A) receptor expression in vascular smooth muscle cells from human placenta: a new ET(A) receptor messenger ribonucleic acid is generated by alternative splicing of exon 3. J. Clin. Endocr. Metab. 82: 3116-3123, 1997. [PubMed: 9284755] [Full Text: https://doi.org/10.1210/jcem.82.9.4209]
Campia, U., Cardillo, C., Panza, J. A. Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients. Circulation 109: 3191-3195, 2004. [PubMed: 15148269] [Full Text: https://doi.org/10.1161/01.CIR.0000130590.24107.D3]
Charite, J., McFadden, D. G., Merlo, G., Levi, G., Clouthier, D. E., Yanagisawa, M., Richardson, J. A., Olson, E. N. Role of Dlx6 in regulation of an endothelin-1-dependent dHAND branchial arch enhancer. Genes Dev. 15: 3039-3049, 2001. [PubMed: 11711438] [Full Text: https://doi.org/10.1101/gad.931701]
Clouthier, D. E., Hosoda, K., Richardson, J. A., Williams, S. C., Yanagisawa, H., Kuwaki, T., Kumada, M., Hammer, R. E., Yanagisawa, M. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125: 813-824, 1998. [PubMed: 9449664] [Full Text: https://doi.org/10.1242/dev.125.5.813]
Cushman, L. J., Torres-Martinez, W., Weaver, D. D. Johnson-McMillin syndrome: report of a new case with novel features. Birth Defects Res. A Clin. Molec. Teratol. 73: 638-641, 2005. [PubMed: 16116593] [Full Text: https://doi.org/10.1002/bdra.20178]
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Gordon, C. T., Weaver, K. N., Zechi-Ceide, R. M., Madsen, E. C., Tavares, A. L. P., Oufadem, M., Kurihara, Y., Adameyko, I., Picard, A., Breton, S., Pierrot, S., and 22 others. Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am. J. Hum. Genet. 96: 519-531, 2015. [PubMed: 25772936] [Full Text: https://doi.org/10.1016/j.ajhg.2015.01.015]
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Hosoda, K., Nakao, K., Tamura, N., Arai, H., Ogawa, Y., Suga, S., Nakanishi, S., Imura, H. Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelin-A receptor. J. Biol. Chem. 267: 18797-18804, 1992. [PubMed: 1326535]
Maggi, M., Barni, T., Fantoni, G., Mancina, R., Pupilli, C., Luconi, M., Crescioli, C., Serio, M., Vannelli, G. B. Expression and biological effects of endothelin-1 in human gonadotropin-releasing hormone-secreting neurons. J. Clin. Endocr. Metab. 85: 1658-1665, 2000. [PubMed: 10770212] [Full Text: https://doi.org/10.1210/jcem.85.4.6565]
Makita, T., Sucov, H. M., Gariepy, C. E., Yanagisawa, M., Ginty, D. D. Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature 452: 759-763, 2008. [PubMed: 18401410] [Full Text: https://doi.org/10.1038/nature06859]
Maurer, M., Wedemeyer, J., Metz, M., Piliponsky, A. M., Weller, K., Chatterjea, D., Clouthier, D. E., Yanagisawa, M. M., Tsai, M., Galli, S. J. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432: 512-516, 2004. [PubMed: 15543132] [Full Text: https://doi.org/10.1038/nature03085]
Miao, J., Wang, F., Fang, Y. Association of 231G-A polymorphism of endothelin type A receptor gene with migraine: a meta-analysis. J. Neurol. Sci. 323: 232-235, 2012. [PubMed: 23058564] [Full Text: https://doi.org/10.1016/j.jns.2012.09.027]
Okafor, M. C., Delamere, N. A. The inhibitory influence of endothelin on active sodium-potassium transport in porcine lens. Invest. Ophthal. Vis. Sci. 42: 1018-1023, 2001. [PubMed: 11274080]
Tzourio, C., El Amrani, M., Poirier, O., Nicaud, V., Bousser, M.-G., Alperovitch, A. Association between migraine and endothelin type A receptor (ETA -231 A/G) gene polymorphism. Neurology 56: 1273-1277, 2001. [PubMed: 11376172] [Full Text: https://doi.org/10.1212/wnl.56.10.1273]
Yanagisawa, H., Hammer, R. E., Richardson, J. A., Williams, S. C., Clouthier, D. E., Yanagisawa, M. Role of endothelin-1/endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J. Clin. Invest. 102: 22-33, 1998. [PubMed: 9649553] [Full Text: https://doi.org/10.1172/JCI2698]
Yanagisawa, H., Yanagisawa, M., Kapur, R. P., Richardson, J. A., Williams, S. C., Clouthier, D. E., de Wit, D., Emoto, N., Hammer, R. E. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125: 825-836, 1998. [PubMed: 9449665] [Full Text: https://doi.org/10.1242/dev.125.5.825]
Zechi-Ceide, R. M., Guion-Almeida, M. L., Jehee, F. S., Rocha, K., Passos-Bueno, M. R. S. Mandibulofacial dysostosis, severe lower eyelid coloboma, cleft palate, and alopecia: a new distinct form of mandibulofacial dysostosis or a severe form of Johnson-McMillin syndrome? Am. J. Med. Genet. 152A: 1838-1840, 2010. [PubMed: 20583178] [Full Text: https://doi.org/10.1002/ajmg.a.33477]
Zeidel, M. L., Brady, H. R., Kone, B. C., Gullans, S. R., Brenner, B. M. Endothelin, a peptide inhibitor of Na(+)-K(+)-ATPase in intact renal tubular epithelial cells. Am. J. Physiol. 257: C1101-C1107, 1989. [PubMed: 2558568] [Full Text: https://doi.org/10.1152/ajpcell.1989.257.6.C1101]