Nature Genetics
12, 445 - 447 (1996)
doi:10.1038/ng0496-445
A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome)Robert M.W. Hofstra1, Jan Osinga1, Gita Tan-Sindhunata1, Ying Wu1, Erik-J. Kamsteeg1, Rein P. Stulp1, Conny van Ravenswaaij-Arts2, Daniëlle Majoor-Krakauer3, Misha Angrist4, Aravinda Chakravarti4, Carel Meijers5
& Charles H.C.M. Buys1, 6
1Department of Medical Genetics, University of Groningen, Ant. Deusinglaan 4, 9713 AW, Groningen, The Netherlands.
2Department of Clinical Genetics, University of Nijmegen, The Netherlands.
3Department of Clinical Genetics, Erasmus University Rotterdam, The Netherlands.
4Department of Genetics, Center for Human Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
5Institute of Paediatric Surgery/Cell Biology and Genetics, Erasmus University Rotterdam, The Netherlands.
6Correspondence should be addressed to C.H.C.M.B. Hirschsprung disease (HSCR) or colonic agan-glionosis 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 gene1−2, which codes for a receptor tyrosine kinase, and in EDNRB3 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)4, 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 syndrome5). 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.
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