A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease

Cell. 1994 Dec 30;79(7):1257-66. doi: 10.1016/0092-8674(94)90016-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CHO Cells
  • Calcium / metabolism
  • Chromosome Mapping
  • Chromosomes, Human, Pair 13
  • Cricetinae
  • Hirschsprung Disease / genetics*
  • Humans
  • Linkage Disequilibrium
  • Molecular Sequence Data
  • Pedigree
  • Point Mutation*
  • Polymorphism, Single-Stranded Conformational
  • Receptor, Endothelin B
  • Receptors, Endothelin / genetics*
  • Transfection


  • Receptor, Endothelin B
  • Receptors, Endothelin
  • Calcium