A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome)

RMW Hofstra, J Osinga, G Tan-Sindhunata, Y Wu… - Nature …, 1996 - nature.com
RMW Hofstra, J Osinga, G Tan-Sindhunata, Y Wu, EJ Kamsteeg, RP Stulp…
Nature genetics, 1996nature.com
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 EDNRB 3 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 …
Abstract
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.
nature.com