title: A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome).
abstract: Hirschsprung disease (HSCR) or colonic aganglionosis is a congenital disorder characterized by an absence of intramural ganglia along variable lengths of the colon resulting in intestinal obstruction. The incidence of HSCR is 1 in 5,000 live births. Mutations in the RET gene, which codes for a receptor tyrosine kinase, and in EDNRB which codes for the endothelin-B receptor, have been shown to be associated with HSCR in humans. The lethal-spotted mouse which has pigment abnormalities, but also colonic aganglionosis, carries a mutation in the gene coding for endothelin 3 (Edn3), the ligand for the receptor protein encoded by EDNRB. Here, we describe a mutation of the human gene for endothelin 3 (EDN3), homozygously present in a patient with a combined Waardenburg syndrome type 2 (WS2) and HSCR phenotype (Shah-Waardenburg syndrome). The mutation, Cys159Phe, in exon 3 in the ET-3 like domain of EDN3, presumably affects the proteolytic processing of the preproendothelin to the mature peptide EDN3. The patient's parents were first cousins. A previous child in this family had been diagnosed with a similar combination of HSCR, depigmentation and deafness. Depigmentation and deafness were present in other relatives. Moreover, we present a further indication for the involvement of EDNRB in HSCR by reporting a novel mutation detected in one of 40 unselected HSCR patients.
authors.affiliation: Department of Medical Genetics, University of Groningen, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Hofstra
authors.forename: J
authors.initials: J
authors.lastname: Osinga
authors.forename: G
authors.initials: G
authors.lastname: Tan-Sindhunata
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: E J
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: R P
authors.initials: RP
authors.lastname: Stulp
authors.forename: C
authors.initials: C
authors.lastname: van Ravenswaaij-Arts
authors.forename: D
authors.initials: D
authors.lastname: Majoor-Krakauer
authors.forename: M
authors.initials: M
authors.lastname: Angrist
authors.forename: A
authors.initials: A
authors.lastname: Chakravarti
authors.forename: C
authors.initials: C
authors.lastname: Meijers
authors.forename: C H
authors.initials: CH
authors.lastname: Buys
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D016232:Endothelins / Q000235:genetics*; D005260:Female; D006627:Hirschsprung Disease / Q000150:complications* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014849:Waardenburg Syndrome / Q000145:classification / Q000150:complications* / Q000235:genetics*
chemical_list: D017931:DNA Primers; D016232:Endothelins; D004247:DNA