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Normal Function
The EDN3 gene provides instructions for making a protein called endothelin 3. Proteins in the endothelin family are produced in various cells and tissues, where they are involved in the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division (proliferation).
Endothelin 3 functions by interacting with another protein, endothelin receptor type B (produced from the EDNRB gene), on the surface of cells. During early development before birth, endothelin 3 and endothelin receptor type B together play an important role in neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo, where they give rise to many different types of cells. In particular, endothelin 3 and its receptor are essential for the formation of nerves in the intestine (enteric nerves) and for the production of specialized cells called melanocytes. Melanocytes produce melanin, a pigment that contributes to skin, hair, and eye color. Melanin is also involved in the normal function of the inner ear.
Health Conditions Related to Genetic Changes
Hirschsprung disease
Variants (also known as mutations) in the EDN3 gene have been found to cause Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Although Hirschsprung disease is a feature of another disorder called Waardenburg syndrome type IV (described below), EDN3 gene variants can also cause Hirschsprung disease in people without Waardenburg syndrome. These variants change one DNA building block (nucleotide) or insert an additional nucleotide in the gene. Changes in the EDN3 gene disrupt the normal function of endothelin 3, preventing it from playing its usual role in the development of enteric nerves. As a result, these cells do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine normally, leading to severe constipation or intestinal blockage.
More About This Health ConditionWaardenburg syndrome
Variants in the EDN3 gene have been identified in people with Waardenburg syndrome type IV (also known as Waardenburg-Hirschsprung disease or Waardenburg-Shah syndrome). This type of Waardenburg syndrome is characterized by changes in skin, hair, and eye coloring; hearing loss; and Hirschsprung disease (described above). EDN3 gene variants change single nucleotides in the gene, preventing the production of a functional endothelin 3 protein. Because active endothelin 3 is necessary for the formation of enteric nerves and melanocytes, these cell types do not form normally during embryonic development. Missing enteric nerves in certain parts of the intestine cause the signs and symptoms of Hirschsprung disease. A lack of melanocytes affects the coloring of skin, hair, and eyes and causes the hearing loss characteristic of Waardenburg syndrome.
More About This Health ConditionOther Names for This Gene
- EDN3_HUMAN
- endothelin 3 precursor
- ET3
- HSCR4
- PPET3
- Preproendothelin-3
- RP4-614C15.1
- WS4B
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell. 1994 Dec 30;79(7):1277-85. doi: 10.1016/0092-8674(94)90018-3. Citation on PubMed
- Duan XL, Zhang XS, Li GW. Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung's disease. World J Gastroenterol. 2003 Dec;9(12):2839-42. doi: 10.3748/wjg.v9.i12.2839. Citation on PubMed or Free article on PubMed Central
- Gazquez E, Watanabe Y, Broders-Bondon F, Paul-Gilloteaux P, Heysch J, Baral V, Bondurand N, Dufour S. Endothelin-3 stimulates cell adhesion and cooperates with beta1-integrins during enteric nervous system ontogenesis. Sci Rep. 2016 Dec 1;6:37877. doi: 10.1038/srep37877. Citation on PubMed or Free article on PubMed Central
- Heuckeroth RO. Finding your way to the end: a tale of GDNF and endothelin-3. Neuron. 2003 Dec 4;40(5):871-3. doi: 10.1016/s0896-6273(03)00763-3. No abstract available. Citation on PubMed
- Kapur RP, Gershon MD, Milla PJ, Pachnis V. The influence of Hox genes and three intercellular signalling pathways on enteric neuromuscular development. Neurogastroenterol Motil. 2004 Apr;16 Suppl 1:8-13. doi: 10.1111/j.1743-3150.2004.00467.x. Citation on PubMed
- Pingault V, Bondurand N, Lemort N, Sancandi M, Ceccherini I, Hugot JP, Jouk PS, Goossens M. A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes? J Med Genet. 2001 Mar;38(3):205-9. doi: 10.1136/jmg.38.3.205. No abstract available. Citation on PubMed or Free article on PubMed Central
- Sanchez-Mejias A, Fernandez RM, Lopez-Alonso M, Antinolo G, Borrego S. New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet Med. 2010 Jan;12(1):39-43. doi: 10.1097/GIM.0b013e3181c371b0. Citation on PubMed
- Shin MK, Levorse JM, Ingram RS, Tilghman SM. The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature. 1999 Dec 2;402(6761):496-501. doi: 10.1038/990040. Citation on PubMed
- Svensson PJ, Von Tell D, Molander ML, Anvret M, Nordenskjold A. A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease. Pediatr Res. 1999 May;45(5 Pt 1):714-7. doi: 10.1203/00006450-199905010-00018. Citation on PubMed
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