PURPOSE: Hirschsprung disease is characterized by the absence of intramural 
ganglion cells in the myenteric and submucosal plexuses within distal intestine, 
because of a fail in the enteric nervous system formations process. 
Endothelin-3-endothelin receptor B signaling pathway is known to play an 
essential role in this process. The aim of this study was to evaluate the 
implication of the EDN3 and EDNRB genes in a series of patients with 
Hirschsprung disease from Spain and determinate their mutational spectrum.
METHODS: We performed the mutational screening of both genes in 196 patients 
with Hirschsprung disease using denaturing high-performance liquid 
chromatography technology. A case-control study using TaqMan Technology was also 
carried out to evaluate some common polymorphisms and haplotypes as 
susceptibility factors for Hirschsprung disease.
RESULTS: Besides several novel mutations in both genes, we found a truncating 
mutation in an alternative isoform of EDNRB. Interestingly, we obtained an 
overrepresentation of a specific EDN3 haplotype in cases versus controls.
CONCLUSIONS: Our results suggest that the isoform EDNRB Delta 3 might be playing 
an essential role in the formation of enteric nervous system. In addition, based 
on the haplotype distribution, EDN3 might be considered as a common 
susceptibility gene for sporadic Hirschsprung disease in a low-penetrance 
fashion.