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

Erik G. Puffenberger, Kiminori Hosoda, Sarah S. Washington, Kazuwa Nakao, Damiane deWit, Masashi Yanagisawa, Aravinda Chakravarti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1257-1266
Number of pages10
JournalCell
Volume79
Issue number7
DOIs
StatePublished - Dec 30 1994

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease'. Together they form a unique fingerprint.

Cite this