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.
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References
Romeo, G. et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's Disease. Nature 367, 377–378 (1994).
Edery, P. et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 367, 378–380 (1994).
Puffenberger, E.G. et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79, 1257–1266 (1994).
Baynash, A. et al. Interaction of endothelin 3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285 (1994).
Omenn, G.S. & McKusick, V.A. Association of Waardenburg syndrome and Hirschsprung megacolon. Am. J. Med. Genet. 3, 217–223 (1979).
Inoue, A. et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc. Nail. Acad. Sci. USA 86, 2863–2867 (1989).
Xu, D. et al. A membrane bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78, 473–485 (1994).
Farrer, L.A. et al. Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes. Am. J. Hum. Genet. 55, 728–737 (1994).
Tassabehji, M., Newton, V.E. & Read, A.P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8, 251–255 (1994).
Lane, R.W. Association of megacolon with two recessive spotting genes in mouse. J. Hered. 57, 29–31 (1966).
Bolande, R.P. Animal model of human disease: Aganglionic megacolon in piebald and spotted mutant mouse strains. Am. J. Pathol. 23, 237–242 (1975).
Hosoda, K. et al. Targeted and natural (Piebald-Lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79, 1267–1276 (1994).
Attie, T. et al. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum. Molec. Genet. 4, 2407–2409 (1995).
Yin, L. et al. Heterogeneity and low detection rate of RET mutations in Hirschsprung disease. Eur. J. Hum. Genet. 2, 272–280 (1994).
Angrist, M. et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum. Molec. Genet. 4, 821–830 (1995).
Attie, T. et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum. Molec. Genet. 4, 1381–1386 (1995).
Lane, R.W. & Liu, H.M. Association of megacolon with a new dominant spotting gene in the mouse. J. Hered. 75, 435–439 (1984).
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Hofstra, R., Osinga, J., Tan-Sindhunata, G. et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 12, 445–447 (1996). https://doi.org/10.1038/ng0496-445
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DOI: https://doi.org/10.1038/ng0496-445