ENDOTHELIN-3 GENE-MUTATIONS IN ISOLATED AND SYNDROMIC HIRSCHSPRUNG-DISEASE

Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent conge nital malformation regarded as a multigenic neurocristopathy. Four sus ceptibility genes have recently been identified in HSCR, namely the RE T proto-oncogene, the glial cell line-derived neurotrophic factor (GDN F), the endothelin B receptor (EDNRB) and the endothelin-3 genes (EDN3 ). Homozygosity for EDN3 mutations has been previously shown to cause the Shah-Waardenburg syndrome, a combination of HSCR with features of the Waardenburg syndrome. Here, we report on heterozygous EDN3 missens e mutations in isolated HSCR. The present data give further support to the role of the endothelin-signaling pathway in the development of ne ural crest-derived enteric neurons. They also suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.