Nature Genetics
12, 442 - 444 (1996)
doi:10.1038/ng0496-442
Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome)Patrick Edery1, Tania Attie1, Jeanne Amiel1, Anna Pelet1, Charis Eng2, Robert M.W. Hofstra3, Helene Martelli1, Christelle Bidaud1, Arnold Munnich1
& Stanislas Lyonnet1, 4
1Service de Génétique Médicale et Unité de Recherchessurles Handicaps Génétiques de l'Enfant, INSERM U-393, Institut Necker, Hôpital des Enfants Malades, 75743 Paris, France.
2Division of Cancer Epidemiology and Control and Division of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
3Department of Medical Genetics, University of Groningen, 9713 AW Groningen, The Netherlands.
4Correspondence should be addressed to S.L. Hirschsprung disease (HSCR) and Waardenburg syndrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells1−3. The WS-HSCR association (Shah-Waardenburg syndrome)4 is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene5,6. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants7. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype8, the EDA/3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDA/3 gene in a WS-HSCR patient. EDA/3 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.
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