MUTATIONS OF THE EDN3 GENE IN ISOLATED AND SYNDROMIC HIRSCHSPRUNGS-DISEASE

Aims and methods. - Hirschsprung's disease is a frequent congenital ma lformation regarded as a multigenic neurocristopathy. Three susceptibi lity genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor an d the endothelin B receptor. A total of 174 probands with isolated Hir schsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 f amilial, 3 sporadic cases) were screened for mutations in the coding s equence of the endothelin 3 gene. The coding sequence of the endotheli n 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing. Results. - Two heterozygous mutat ions (A17T and A224T) were identified in two patients with isolated Hi rschsprung's disease. Two homozygous truncations mutations (E55X and G C262- > T) were identified in patients with the Waardenburg's syndrome /Hirschsprung's disease association. Conclusion. - The present data gi ve further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also sug gest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.