Journal
GENETICS IN MEDICINE
Volume 12, Issue 1, Pages 39-43Publisher
NATURE PUBLISHING GROUP
DOI: 10.1097/GIM.0b013e3181c371b0
Keywords
Hirschsprung disease; enteric nervous system; EDNRB; EDN3; complex disease
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Funding
- Fondo de Investigacion Sanitaria, Spain [PI070080, PI071315]
- Consejeria de Innovacion Ciencia y Empresa [CTS 2590)]
- Consejeria de Salud de la Junta de Andalucia [PI0249-2008]
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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. Genet Med 2010:12(1):39-43.
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