title: Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease.
abstract: Waardenburg syndrome (WS) comprises sensorineural hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides. Four types of WS have been classified to date; in WS type IV (WS4), patients additionally have colonic aganglionosis (Hirschsprung disease, HSCR). Mutations in the endothelin-3 (EDN3), endothelin-B receptor (EDNRB), and Sox10 genes have been identified as causative for WS type IV. We screened a family with a combined WS-HSCR phenotype for mutations in the EDNRB locus using standard DNA mutation analysis and sequencing techniques. We have identified a novel nonsense mutation at codon 253 (CGA-->TGA, Arg-->STOP). This mutation leads to a premature end of the translation of EDNRB at exon 3, and it is predicted to produce a truncated and nonfunctional endothelin-B receptor. All affected relatives were heterozygous for the Arg(253)-->STOP mutation, whereas it was not observed in over 50 unrelated individuals used as controls. These data confirm the role of EDNRB in the cause of the Waardenburg-Hirschsprung syndrome and demonstrate that in WS-HSCR there is a lack of correlation between phenotype and genotype and a variable expression of disease even within the same family.
authors.affiliation: Medical Genetics Unit, St. George's Hospital Medical School, London, United Kingdom. p.syrris@sghms.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: Syrris
authors.forename: N D
authors.initials: ND
authors.lastname: Carter
authors.forename: M A
authors.initials: MA
authors.lastname: Patton
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin