Disease	Score

Substances	Interaction	Organism	Category

Substances	Interaction	Organism	Category

     Hirschsprung disease About 10 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 mutations can also cause Hirschsprung disease in people without Waardenburg syndrome. These mutations 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. Waardenburg syndrome At least five mutations in the EDN3 gene have been identified in people with Waardenburg syndrome type IV (also known as Waardenburg-Shah syndrome). This type of Waardenburg syndrome is characterized by changes in skin, hair, and eye coloring; hearing loss; and Hirschsprung disease. EDN3 mutations 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.

     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. 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.

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

The following transcription factors affect gene expression:

• AP-1
• AhR
• c-Jun
• HNF-4alpha1
• HNF-4alpha2

Tissue specificity:

Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells.

Molecular Function:

• Receptor Binding
• Hormone Activity
• Endothelin B Receptor Binding

Biological Processes:

• Neural Crest Cell Migration
• Positive Regulation Of Leukocyte Chemotaxis
• Regulation Of Systemic Arterial Blood Pressure By Endothelin
• Cellular Calcium Ion Homeostasis
• Signal Transduction
• Cell Surface Receptor Signaling Pathway
• Cell-Cell Signaling
• Multicellular Organism Development
• Blood Circulation
• Positive Regulation Of Cell Proliferation
• Positive Regulation Of Heart Rate
• Regulation Of Gene Expression
• Cellular Magnesium Ion Homeostasis
• Vein Smooth Muscle Contraction
• Regulation Of Vasoconstriction
• Peptide Hormone Secretion
• Neuron Differentiation
• Melanocyte Differentiation
• Neutrophil Chemotaxis
• Vasoconstriction
• Positive Regulation Of Map Kinase Activity
• Positive Regulation Of Cell Differentiation
• Positive Regulation Of Mitotic Nuclear Division
• Positive Regulation Of Hormone Secretion
• Inositol Phosphate-Mediated Signaling
• Regulation Of Developmental Pigmentation
• Positive Regulation Of Potassium Ion Transmembrane Transport

*synonyms