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

doi:10.1016/0092-8674(94)90016-7

Cell

Volume 79, Issue 7, 30 December 1994, Pages 1257-1266

https://doi.org/10.1016/0092-8674(94)90016-7 Get rights and content

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.

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Citation Excerpt :
Mutations in EDNRB were shown to be associated with human Hirschsprung disease, and have been demonstrated in approximately 5% of this disease.27,88–91 W276C ETBR variant was first identified from Mennonite kindred with a high incidence of Hirschsprung disease.27 Since then, 46 additional EDNRB mutations have been reported, including M1V, L17P, K15X, P48L, K56T, G57S, C90R, N104I, C109R, V111Q, G115R, M132I, R133X, N137Y, P156S, P156R, I157V, M173T, C174Y, A183G, V185M, G186R, S196N, R201X, W226C, W226X, T244N, D246F, R253X, V260F, W275X, W276C, Y293fs, Y293L, S305N, A310T, R319W, C335S, L361S, M374I, N378fs, N378S, N378I, P383L, S390R, and R434C8,89–108 (Fig. 4).
G protein-coupled receptors (GPCRs) are the largest family of cell membrane receptors involved in modulating almost all physiological processes by transducing extracellular signals into the cytoplasm. Dysfunctions of GPCR-regulated signaling result in diverse human diseases, making GPCRs the most popular drug targets for human medicine. Large animals share higher similarities (in physiology and metabolism) with humans than rodents. Similar to findings in human genetics, diverse diseases caused by mutations in GPCR genes have also been discovered in large animals. Rhodopsin, endothelin B receptor, and CC chemokine receptor type 5 have been shown to be involved in human retinitis pigmentosa, Hirschsprung disease, and HIV infection/AIDS, respectively, and several mutations of these GPCRs have also been identified from large animals. The large animals with naturally occurring mutations of these GPCRs provide an opportunity to gain a better understanding of the pathogenesis of human diseases, and can be used for preclinical trials of therapies for human diseases. In this review, we aim to summarize the naturally occurring mutations of these three GPCRs in large animals and humans.

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^†: The first two authors contributed equally to this study.

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Cell

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

Abstract

J. Biol. Chem.

J. Biol. Chem.

Gastroenterology

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Genomics

Cell

A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10

Nature Genet.

Cloning and expression of a cDNA encoding an endothelin receptor

Nature

Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3

Am. J. Hum. Genet.

Waardenburg syndrome and Hirschsprung disease: evidence for pleiotropic effects of a single gene

Am. J. Med. Genet.

A genetic study of Hirschsprung disease

Am. J. Hum. Genet.

Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons

Cell

Mutational analysis of human endothelin receptors ETa and ETB: identification of regions involved in the selectivity for endothelin 3 or cyclo-(D-Trp-d-Asp-Pro-d-Val-Leu)

Eur. J. Biochem.

The early settlement of Waterloo Township, Ontario, Canada

Penn. Mennonite Herit.

A case of Hirschsprung disease with a chromosome 13 microdeletion, del(13)(q32.3q33.2): potential mapping of one disease locus

Hum. Genet.

DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the RET proto-oncogene

Oncogene

A theory for radiation hybrid (Gross-Harris) mapping: application to proximal 21q markers

Cytogenet. Cell Genet.

Why testicles are cool

Nature

A first-generation physical map of the human genome

Nature

A vascular cause for aganglionic bowel: a new hypothesis

Am. J. Digest. Dis.

Mutations of the RET proto-oncogene in Hirschsprung's disease

Nature

Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus

J. Med. Genet.

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

Mutational analysis of human endothelin receptors ET_a and ET_B: identification of regions involved in the selectivity for endothelin 3 or cyclo-(D-Trp-d-Asp-Pro-d-Val-Leu)