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 journalArticle

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
Externally publishedYes

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Endothelin B Receptors
Hirschsprung Disease
Missense Mutation
Genes
Homozygote
Human Chromosomes
Pedigree
Heterozygote
Chromosomes
G-Protein-Coupled Receptors
Ganglia
Gastrointestinal Tract
Exons
Colon
Genotype
Ligands
Mutation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Puffenberger, E. G., Hosoda, K., Washington, S. S., Nakao, K., deWit, D., Yanagisawa, M., & Chakravarti, A. (1994). A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease. Cell, 79(7), 1257-1266. https://doi.org/10.1016/0092-8674(94)90016-7

A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease. / Puffenberger, Erik G.; Hosoda, Kiminori; Washington, Sarah S.; Nakao, Kazuwa; deWit, Damiane; Yanagisawa, Masashi; Chakravarti, Aravinda.

In: Cell, Vol. 79, No. 7, 30.12.1994, p. 1257-1266.

Research output: Contribution to journalArticle

Puffenberger, EG, Hosoda, K, Washington, SS, Nakao, K, deWit, D, Yanagisawa, M & Chakravarti, A 1994, 'A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease', Cell, vol. 79, no. 7, pp. 1257-1266. https://doi.org/10.1016/0092-8674(94)90016-7
Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M et al. A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease. Cell. 1994 Dec 30;79(7):1257-1266. https://doi.org/10.1016/0092-8674(94)90016-7
Puffenberger, Erik G. ; Hosoda, Kiminori ; Washington, Sarah S. ; Nakao, Kazuwa ; deWit, Damiane ; Yanagisawa, Masashi ; Chakravarti, Aravinda. / A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease. In: Cell. 1994 ; Vol. 79, No. 7. pp. 1257-1266.
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