TY - JOUR
T1 - A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease
AU - Puffenberger, Erik G.
AU - Hosoda, Kiminori
AU - Washington, Sarah S.
AU - Nakao, Kazuwa
AU - deWit, Damiane
AU - Yanagisawa, Masashi
AU - Chakravarti, Aravinda
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/12/30
Y1 - 1994/12/30
N2 - 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.
AB - 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.
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U2 - 10.1016/0092-8674(94)90016-7
DO - 10.1016/0092-8674(94)90016-7
M3 - Article
C2 - 8001158
AN - SCOPUS:0028618372
SN - 0092-8674
VL - 79
SP - 1257
EP - 1266
JO - Cell
JF - Cell
IS - 7
ER -