title: Significance of novel endothelin-B receptor gene polymorphisms in Hirschsprung's disease: predominance of a novel variant (561C/T) in patients with co-existing Down's syndrome.
abstract: Several genes have been implicated in the pathogenesis of Hirschsprung's disease (HSCR). In a previous study performed, five novel (V202M, E480K, IVS10-2A/G, D771N, IVS19-9C/T) mutations and one previously described mutation (P937L) have been identified in the RET proto-oncogene in 20% of the study population. To further investigate the involvement of other genes, mutation analysis of the endothelin-B receptor (EDNRB) gene was performed in 52 unrelated sporadic HSCR patients, including 38 non-syndromic and 14 patients with HSCR and Down's syndrome. Six novel (178G/A, 552C/T, 561C/T, 702C/T, IVS3-6C/T and IVS4 + 3A/G) sequence variants and one previously described (831G/A) polymorphism were identified. Statistically significant differences were achieved for six (178G/A, 552C/T, 561C/T, 702C/T, IVS3-6C/T and 831G/A) of these variants. The T-allele of the 561C/T polymorphism was over represented in the HSCR/Down's syndrome patient group (36% representing 5 of 14) compared to normal controls (6% representing 5 of 84) (p < 0.002, chi(2) with Yates correction = 12.14), suggesting that the 561C/T variant is associated with a low penetrance effect in patients with this complex phenotype. Detection of the 178G/A polymorphism in only non-syndromic HSCR patients, provide further support for an important role of specific sequence variants in the EDNRB gene in the HSCR/Down's syndrome phenotype.
authors.affiliation: Division of Human Genetics, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. mjulies@sun.ac.za
authors.forename: M G
authors.initials: MG
authors.lastname: Zaahl
authors.forename: L
authors.initials: L
authors.lastname: du Plessis
authors.forename: L
authors.initials: L
authors.lastname: Warnich
authors.forename: M J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: S W
authors.initials: SW
authors.lastname: Moore
mesh_terms: D004314:Down Syndrome / Q000150:complications*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006627:Hirschsprung Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D017354:Point Mutation; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D044023:Receptor, Endothelin B / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D044023:Receptor, Endothelin B