The EDNRB gene encodes a non-specific, G protein-coupled receptor for endothelin 1, 2, and 3. Once activated through ligand binding, this G protein-coupled receptor known as Endothelin Receptor Type B regulates several biological processes including differentiation of melanocytes, development of enteric nervous system, migration of neural crest cells, vasoconstriction/vasodilation, and sensory perception of pain.
Mutations in EDNRB gene are associated with Waardenburg Syndrome Type 4A and Hirschsprung Disease 2.
In 1999, Brooks et al. reported three children from a large, consanguineous, Moroccan family with Hirschsprung disease, mental retardation, microcephaly, and specific craniofacial dysmorphism. Goldberg-Shprintzen syndrome (Mowat-Wilson syndrome) was suspected due to the association of these abnormalities in the children. Mutation scanning of genes involved in Hirschsprung disease - RET, GDNF, EDN3, and EDNRB, showed a sequence variant, Ser305Asn, in exon 4 of the EDNRB gene in the index patient of this family. The Ser305Asn was also identified in two of the four patients and four healthy relatives. As this mutation wasn't present in all the patients from the family, Brooks et al. (1999) suggested that the EDNRB variant is unlikely to contribute to the phenotype and that the family might benefit from identification of a Goldberg-Shprintzen locus.
In two girls born to consanguineous Tunisian parents, Attie et al. (1995) described features of both Waardenburg syndrome and Hirschsprung disease. They excluded RET and PAX3 as candidate genes by linkage analysis but found a homozygous missense mutation in exon 2 of the EDNRB gene. Using microsatellite DNA markers flanking the EDNRB gene, they showed that the two affected sibs were geno-identical and homozygous at these loci, whereas the two unaffected brothers shared no more than one allele with their affected sisters. The affected sisters showed an abnormal SSCP pattern in exon 2 and direct DNA sequencing revealed a C>G transversion at the second nucleotide of codon 183, predicted to result in the replacement of an alanine by a glycine (p.A183G) in the third transmembrane domain of EDNRB. The parents and one healthy brother were heterozygous for the p.A183G mutation.