New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease

Genet Med. 2010 Jan;12(1):39-43. doi: 10.1097/GIM.0b013e3181c371b0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • DNA Mutational Analysis
  • Down Syndrome / complications
  • Down Syndrome / genetics
  • Endothelin-3 / genetics*
  • Female
  • Frameshift Mutation
  • Genetic Variation
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Receptor, Endothelin B / genetics*
  • Reference Values
  • Sequence Deletion


  • Endothelin-3
  • Receptor, Endothelin B