EDNRB

Variants (also known as mutations) in the EDNRB 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 condition called Waardenburg syndrome type IV (described below), EDNRB gene variants can also cause Hirschsprung disease in people without Waardenburg syndrome. People with a variant in one of the two copies of the EDNRB gene tend to develop Hirschsprung disease, while people with variants in both copies of the gene usually develop Waardenburg syndrome type IV. Most of these variants change single DNA building blocks (nucleotides) in the gene. Changes in the EDNRB gene disrupt the normal function of endothelin receptor type B, 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.

Variants in the EDNRB 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). Variants in the EDNRB gene disrupt the normal function of endothelin receptor type B or lead to the production of an abnormally small, nonfunctional version of the protein. Because the receptor 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.

Several studies have suggested that inherited variations in the EDNRB gene may be associated with an increased risk of melanoma, a common form of skin cancer that begins in melanocytes. However, other studies have not shown this association, and this gene's role in cancer risk remains unclear.