title: A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease.
abstract: Hirschsprung's disease (HSCR) is characterized by an absence of enteric ganglia in the distal colon and a failure of innervation in the gastrointestinal tract. We recently mapped a recessive susceptibility locus (HSCR2) to human chromosome 13q22, which we now demonstrate to be the endothelin-B receptor gene (EDNRB). We identified in HSCR patients a G-->T missense mutation in EDNRB exon 4 that substitutes the highly conserved Trp-276 residue in the fifth transmembrane helix of the G protein-coupled receptor with a Cys residue (W276C). The mutant W276C receptor exhibited a partial impairment of ligand-induced Ca2+ transient levels in transfected cells. The mutation is dosage sensitive, in that W276C homozygotes and heterozygotes have a 74% and a 21% risk, respectively, of developing HSCR. Genotype analysis of patients in a Mennonite pedigree shows HSCR to be a multigenic disorder.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Ohio 44106-4955.
authors.forename: E G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: K
authors.initials: K
authors.lastname: Hosoda
authors.forename: S S
authors.initials: SS
authors.lastname: Washington
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: D
authors.initials: D
authors.lastname: deWit
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: A
authors.initials: A
authors.lastname: Chakravart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D006224:Cricetinae; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D014162:Transfection
chemical_list: D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D002118:Calcium