Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease

Hirschsprung's disease (HSCR) is characterized by the absence of autonomicganglion cells in the terminal bowel and is a relatively common cause ofintestinal obstruction in the newborn. The incidence of HSCR is estimatedto be 1 in 5000 live births. Recently, the endothelin- B receptor (EDNRB)gene has been shown as a susceptibility gene for HSCR by the production ofaganglionic colon in mice with a null mutation of this gene and bydemonstrating a missense mutation in a large inbred kindred with a highincidence of HSCR (Mennonite pedigree). However, no further mutations havebeen demonstrated in other clinical cases. We analysed alterations of theEDNRB gene in 41 isolated patients of HSCR. Two novel mutations weredetected: a G to A transition at nucleotide 824 and an insertion of T atnucleotide 878. Both mutations resulted in stop codons, predicted toproduce a truncated and non-functional endothelin-B receptor. Theseobservations indicate that dysfunction or loss of function of endothelin-Breceptor may be involved in the aetiology of some isolated patients withHSCR.