Novel nonsense mutation of the endothelin-B receptor gene in a family withWaardenburg-Hirschsprung disease

Waardenburg syndrome (WS) comprises sensorineural hearing loss, hypopigment ation of skin and hair, and pigmentary disturbances of the irides. Four typ es of WS have been classified to date; in WS type IV (WS4), patients additi onally have colonic aganglionosis (Hirschsprung disease, HSCR). Mutations i n the endothelin-3 (EDN3), endothelin-B receptor (EDNRB), and Sox10 genes h ave 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 standar d DNA mutation analysis and sequencing techniques. We have identified a nov el nonsense mutation at codon 253 (CGA-->TGA, Arg-->STOP). This mutation le ads to a premature end of the translation of EDNRB at exon 3, and it is pre dicted to produce a truncated and nonfunctional endothelin-B receptor. All affected relatives were heterozygous for the Arg(253)-->STOP mutation, wher eas 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-Hirsch sprung syndrome and demonstrate that in WS-HSCR there is a lack of correlat ion between phenotype and genotype and a variable expression of disease eve n within the same family, Am. J. Med. Genet. 87:69-71, 1999. (C) 1999 Wiley -Liss, Inc.