Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome)

Nat Genet. 1996 Apr;12(4):442-4. doi: 10.1038/ng0496-442.


Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Child, Preschool
  • DNA / genetics
  • Endothelins / genetics*
  • Endothelins / physiology
  • Female
  • Genes, Recessive
  • Hirschsprung Disease / complications*
  • Hirschsprung Disease / etiology
  • Hirschsprung Disease / genetics*
  • Homozygote
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Neural Crest / growth & development
  • Phenotype
  • Waardenburg Syndrome / complications*
  • Waardenburg Syndrome / etiology
  • Waardenburg Syndrome / genetics*


  • Endothelins
  • DNA