[Mutations of the endothelin-3 gene in isolated and syndromic forms of Hirschsprung disease].

AIMS AND METHODS

Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing.

RESULTS

Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262->T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association.

CONCLUSION

The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.