Alternative titles; symbols
HGNC Approved Gene Symbol: EDN3
Cytogenetic location: 20q13.32 Genomic coordinates (GRCh38) : 20:59,300,611-59,325,992 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.32 | {Hirschsprung disease, susceptibility to, 4} | 613712 | Autosomal dominant | 3 |
| Waardenburg syndrome, type 4B | 613265 | Autosomal dominant; Autosomal recessive | 3 |
In addition to the gene for vasoactive peptide endothelin-1 (EDN1; 131240), Inoue et al. (1989) found 2 human genomic fragments that potentially encode related vasoconstricted peptides and called them endothelin-2 (EDN2; 131241) and endothelin-3 (EDN3). Only EDN1 gene expression was observed in endothelial cells.
Bloch et al. (1989) documented transcription of the EDN3 gene, which they called ET3, by isolating from a hypothalamic cDNA library, DNA clones complementary to human EDN3 mRNA, which encodes a 230-amino acid precursor that includes the biologically active 21-amino acid EDN3 and a 15-amino acid homologous segment called the endothelin-like sequence. They made further observations on expression of the genes in different tissues.
Lee et al. (1999) demonstrated that the Kell blood group protein (613883) is involved in the proteolytic processing of big endothelin-3 at trp21/ile22, yielding ET3.
Dupin et al. (2000) found that in vitro ET3 exerts a dose-dependent stimulation of proliferation and melanogenesis in neural crest cells that had homed to the epidermis of embryonic quail dorsal skin. Moreover, in clonal cultures of skin-derived pigment cells, ET3 induced rapid cell divisions of clonogenic melanocytes that generated a mixed progeny of melanocytes and cells devoid of pigment granules and expressing glial markers in more than 40% of the colonies. They concluded that ET3 is strongly mitogenic to embryonic pigment cells and can alter their differentiation program, leading them to recapitulate the glial-melanocyte bipotentiality of their neural crest ancestors.
Makita et al. (2008) demonstrated in mouse embryos that the endothelium family member Edn3, acting through the endothelin receptor EdnrA (131243), 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, they suggested a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.
By analysis of DNA isolated from human-mouse somatic cell hybrid lines, Bloch et al. (1989) assigned the EDN3 gene to human chromosome 20. Rao et al. (1991) confirmed the assignment of EDN3 to chromosome 20 by study of human-mouse somatic cell hybrids and localized the gene to 20q13.2-q13.3 by in situ hybridization. By Southern blot analysis of somatic cell hybrid DNAs and by in situ hybridization, Arinami et al. (1991) also mapped EDN3 to 20q13.2-q13.3. By analysis of an interspecific backcross, Malas et al. (1994) demonstrated that the mouse homolog maps to chromosome 2 in a region of conserved synteny with human chromosome 20.
Waardenburg Syndrome Type 4B
In a patient with Waardenburg syndrome type 4B (WS4B; 613265), a form of Waardenburg-Shah syndrome, Edery et al. (1996) identified a homozygous substitution/deletion mutation of the EDN3 gene (131242.0001). Simultaneously and independently, Hofstra et al. (1996) identified a homozygous missense mutation in the EDN3 gene (131242.0002) in a patient with WS4B. Mice mutant for Edn3 display a phenotype similar to that seen in humans with Waardenburg-Shah syndrome (Baynash et al., 1994).
Pingault et al. (2001) identified a heterozygous nonsense mutation in the EDN3 gene (C169X; 131242.0007) in a child with Waardenburg-Shah syndrome. Pingault et al. (2001) noted that this mutation was also found in unaffected family members and in an aborted fetus with a sonographically determined intestinal obstruction.
Susceptibility to Hirschsprung Disease 4
Bidaud et al. (1997) reported a sporadic case of isolated Hirschsprung disease (HSCR4; 613712) with a heterozygous EDN3 missense mutation (131242.0004). The finding gave support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggested the possibility that either recessive or weakly penetrant dominant alleles can occur at the EDN3 locus, depending on the nature of the mutation.
Sanchez-Mejias et al. (2010) screened the EDN3 and EDNRB (131244) genes in 196 patients with Hirschsprung disease from Spain using high performance liquid chromatography. They detected 11 sequence variants in the EDN3 gene among the patients, including 4 novel variants. They also found novel mutations in the EDNRB gene, including a truncating mutation (see 131244.0009) in an alternative isoform.
Reclassified Variants
The 1-bp insertion (131242.0003) reported by Bolk et al. (1996) has been reclassified as a variant of unknown significance. In a patient with isolated congenital central hypoventilation syndrome (CCHS; 209880), Bolk et al. (1996) identified a 1-bp insertion of an adenosine in exon 4 of the EDN3 gene, which caused a frameshift and a premature stop codon in exon 5. The termination resulted in the truncation of the last 41 amino acids of the protein. The insertion occurred within a run of 6 adenines.
Defects in the gene encoding the endothelin-B receptor (131244) result in aganglionic megacolon and pigmentary disorders in mice and humans. Baynash et al. (1994) found that targeted disruption of the mouse endothelin-B ligand (Edn3) gene produces a similar recessive phenotype of megacolon and coat color spotting. The findings indicated that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages. They postulated that defects in the human EDN3 gene may cause Hirschsprung disease.
Kaelin et al. (2012) identified nonsense mutations in the feline Taqpep gene (610046) that segregated with large, dark, and blotchy tabby coat pattern in domestic cats and with enlarged blotchy spots and dorsal stripes in king cheetahs. Expression of Edn3, but not Taqpep, was upregulated in dark compared to light cheetah or neonatal tabby cat skin. In transgenic mice, expression of Edn3 induced darkening of coat color, with increased expression in melanocyte-specific genes. Melanocyte-specific genes were also overexpressed in black-colored areas of cheetah skin. Kaelin et al. (2012) proposed a model whereby Taqpep establishes the periodicity of coat markings during fetal development that are maintained by variable expression of Edn3 through subsequent hair cycles.
In a child with Waardenburg syndrome type 4B (WS4B; 613265), Edery et al. (1996) demonstrated a homozygous substitution/deletion mutation in the EDN3 gene. The 4-year-old girl, born to unrelated parents, had total colonic aganglionosis, bilateral sensorineural hearing loss, and pigmentary anomalies, including achromic patches of the skin, white eyelashes, and pale blue retina, but absence of dystopia canthorum found in Waardenburg syndrome type 1 (193500). The mutation (designated 262GC-T by the authors) was located in exon 2 of the EDN3 gene. The mutation modified the 120 downstream amino acids and resulted in premature translation termination.
Hofstra et al. (1996) screened 40 unselected Hirschsprung disease patients, including both sporadic and familial cases, from mutations in EDN3 and EDNRB (131244). In 1 patient with features combining those of Waardenburg syndrome and Hirschsprung disease (WS4B; 613265), a DGGE variant of exon 3 of EDN3 was detected. Sequencing revealed a homozygous G-to-T transversion leading to a substitution of a phenylalanine for a cysteine in codon 159 (C159F), in the ET3-like domain of the preproendothelin but not in the ET3 domain of the eventual mature peptide. Presumably, the mutation affected the proteolytic processing of the preproendothelin to the mature peptide. The patient's parents were first cousins. A previous child in this family had been diagnosed with a similar combination of Hirschsprung disease, depigmentation, and deafness. Depigmentation and deafness were present in other relatives.
This variant, formerly titled CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, has been reclassified based on its allele frequency in the gnomAD database (v2.1.1) (Hamosh, 2021).
In a patient with isolated congenital central hypoventilation syndrome (CCHS; 209880), Bolk et al. (1996) identified a 1-bp insertion of an adenosine in exon 4 of the EDN3 gene, which caused a frameshift and a premature stop codon in exon 5. The termination resulted in the truncation of the last 41 amino acids of the protein. The insertion occurred within a run of 6 adenines.
Hamosh (2021) noted that the allele frequency of this variant in gnomAD (v2.1.1) is too high to account for a severe pediatric disorder. Its highest frequency was 0.006012 in Finnish Europeans, where it was present in 151 of 25,118 alleles and seen in homozygosity twice.
In a patient with isolated and sporadic Hirschsprung disease (HSCR4; 613712), Bidaud et al. (1997) demonstrated a G-to-A transition in exon 1 of the EDN3 gene at codon 17, resulting in an ala17-to-thr (A17T) missense mutation. The mutation was located in the peptide signal sequence and was inherited from the asymptomatic mother.
Lek et al. (2016) questioned the validity of this variant as a susceptibility allele because it has a high allele frequency (0.0149) in the Latino population in the ExAC database.
In a patient with isolated and sporadic Hirschsprung disease (HSCR4; 613712), Bidaud et al. (1997) detected a G-to-A transition in exon 5 of the EDN3 gene at codon 224, predicted to result in an ala224-to-thr (A224T) amino acid substitution in preproendothelin. The mutation was inherited from the asymptomatic mother.
In a patient with short-segment Hirschsprung disease (HSCR4; 613712) without any Waardenburg features, Svensson et al. (1999) found a novel heterozygous mutation in exon 2 of the EDN3 gene, i.e., an insert of a G after nucleotide 262 of the EDN3 cDNA. The mutation was inherited from the mother, who had a history of moderate constipation from time to time. This frameshift resulted in a premature stop 2 codons farther on. The mutation was predicted to result in haploinsufficiency.
In a child with Waardenburg syndrome type 4B (WS4B; 613265), Pingault et al. (2001) identified a heterozygous C-to-A transversion in the EDN3 gene that introduced a stop codon at position 169 (C169X). This mutation lies within the endothelin-like peptide, which may play a role in the first enzymatic cleavage step of preproendothelin. This mutation was also present in unaffected relatives and in a sib pregnancy, terminated at 29 weeks' gestation, with a sonographically determined intestinal obstruction.
In a Spanish boy, born of consanguineous parents, with Waardenburg syndrome type 4B (WS4B; 613265), Vinuela et al. (2009) identified a homozygous 335A-G transition in exon 2 of the EDN3 gene, resulting in a his112-to-arg (H112R) substitution in a highly conserved residue affecting the active peptide. The mutation was not found in 95 controls. The patient had pale blue irides, white forelock, depigmented skin patches, total colonic aganglionosis, and profound hearing loss. His father and paternal grandmother, who were each heterozygous for the mutation, had white forelocks. Vinuela et al. (2009) were not able to distinguish whether the mild manifestations in the heterozygous carriers were due to haploinsufficiency or a mild dominant-negative effect.
In an Egyptian boy with Waardenburg syndrome type 4B (WS4B; 613265), born of consanguineous parents, Shamseldin et al. (2010) identified a homozygous 277C-G transversion in exon 2 of the EDN3 gene, resulting in an arg93-to-gly (R93G) substitution. The mutation occurred in a highly conserved residue that forms part of the consensus sequence (R-X-X-R) known to be essential for furin (136950) cleaving activity, which is critical for proteolytic cleavage of preproendothelin. The patient had pigmentary abnormalities and Hirschsprung disease, as well as microtia and generalized failure to thrive.
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Bloch, K., Eddy, R. L., Shows, T. B., Quertermous, T. cDNA cloning and chromosomal assignment of the gene encoding endothelin 3. J. Biol. Chem. 264: 18156-18161, 1989. [PubMed: 2509452]
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Dupin, E., Glavieux, C., Vaigot, P., Le Douarin, N. M. Endothelin 3 induces the reversion of melanocytes to glia through a neural crest-derived glial-melanocytic progenitor. Proc. Nat. Acad. Sci. 97: 7882-7887, 2000. [PubMed: 10884419] [Full Text: https://doi.org/10.1073/pnas.97.14.7882]
Edery, P., Attie, T., Amiel, J., Pelet, A., Eng, C., Hofstra, R. M. W., Martelli, H., Bidaud, C., Munnich, A., Lyonnet, S. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nature Genet. 12: 442-444, 1996. [PubMed: 8630502] [Full Text: https://doi.org/10.1038/ng0496-442]
Hamosh, A. Personal Communication. Baltimore, Md. August 17, 2021.
Hofstra, R. M. W., Osinga, J., Tan-Sindhunata, G., Wu, Y., Kamsteeg, E.-J., Stulp, R. P., van Ravenswaaij-Arts, C., Majoor-Krakauer, D., Angrist, M., Chakravarti, A., Meijers, C., Buys, C. H. C. M. A homozygous mutation in the endothelin-3 gene associated with a combined Hirschsprung type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12: 445-447, 1996. [PubMed: 8630503] [Full Text: https://doi.org/10.1038/ng0496-445]
Inoue, A., Yanagisawa, M., Kimura, S., Kasuya, Y., Miyauchi, T., Goto, K., Masaki, T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc. Nat. Acad. Sci. 86: 2863-2867, 1989. [PubMed: 2649896] [Full Text: https://doi.org/10.1073/pnas.86.8.2863]
Kaelin, C. B., Xu, X., Hong, L. Z., David, V. A., McGowan, K. A., Schmidt-Kuntzel, A., Roelke, M. E., Pino, J., Pontius, J., Cooper, G. M., Manuel, H., Swanson, W. F., and 11 others. Specifying and sustaining pigmentation patterns in domestic and wild cats. Science 337: 1536-1541, 2012. [PubMed: 22997338] [Full Text: https://doi.org/10.1126/science.1220893]
Lee, S., Lin, M., Mele, A., Cao, Y., Farmar, J., Russo, D., Redman, C. Proteolytic processing of big endothelin-3 by the Kell blood group protein. Blood 94: 1440-1450, 1999. [PubMed: 10438732]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
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]
Malas, S., Peters, J., Abbott, C. The genes for endothelin 3, vitamin D 24-hydroxylase, and melanocortin 3 receptor map to distal mouse chromosome 2, in the region of conserved synteny with human chromosome 20. Mammalian Genome 5: 577-579, 1994. [PubMed: 8000144] [Full Text: https://doi.org/10.1007/BF00354934]
Pingault, V., Bondurand, N., Lemort, N., Sancandi, M., Ceccherini, I., Hugot, J.-P., Jouk, P.-S., Goossens, M. A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes? (Letter) J. Med. Genet. 38: 205-208, 2001. [PubMed: 11303518] [Full Text: https://doi.org/10.1136/jmg.38.3.205]
Rao, V. V. N. G., Loffler, C., Hansmann, I. The gene for the novel vasoactive peptide endothelin 3 (EDN3) is localized to human chromosome 20q13.2-qter. Genomics 10: 840-841, 1991. [PubMed: 1889823] [Full Text: https://doi.org/10.1016/0888-7543(91)90472-q]
Sanchez-Mejias, A., Fernandez, R. M., Lopez-Alonso, M., Antinolo, G., Borrego, S. New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet. Med. 12: 39-43, 2010. [PubMed: 20009762] [Full Text: https://doi.org/10.1097/GIM.0b013e3181c371b0]
Shamseldin, H. E., Rahbeeni, Z., Alkuraya, F. S. Perturbation of the consensus activation site of endothelin-3 leads to Waardenburg syndrome type IV. (Letter) Am. J. Med. Genet. 152A: 1841-1843, 2010. [PubMed: 20583152] [Full Text: https://doi.org/10.1002/ajmg.a.33123]
Svensson, P.-J., Von Tell, D., Molander, M.-L., Anvret, M., Nordenskjold, A. A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease. Pediat. Res. 45: 714-717, 1999. [PubMed: 10231870] [Full Text: https://doi.org/10.1203/00006450-199905010-00018]
Vinuela, A., Morin, M., Villamar, M., Morera, C., Lavilla, M. J., Cavalle, L., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. (Letter) Am. J. Med. Genet. 149A: 2296-2302, 2009. [PubMed: 19764030] [Full Text: https://doi.org/10.1002/ajmg.a.33026]