Several missense mutations of the endothelin-B receptor (EDNRB) associated with 
Hirschsprung disease have recently been identified. Five mutated EDNRB (A183G, 
W276C, R319W, M374I and P383L) cDNAs were transiently expressed in several cell 
lines to examine the effects of these mutations. Ligand-receptor binding 
experiments demonstrated that all mutants examined here accept endothelins with 
a high affinity. Especially, the affinity of endothelins to P383L was increased. 
However, the number of binding sites of A183G, W276C and P383L was markedly 
decreased. The subcellular localization of these mutant receptors was the same 
as that of wild-type EDNRB, whereas the amount of protein of each mutant 
receptor was decreased. All mutant receptors were impaired in intracellular 
Ca(2+) mobilization. These findings indicate that these missense mutations 
result in loss of function of EDNRB, and may provide the molecular pathological 
basis of Hirschsprung disease in some individuals.