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Titolo:
Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease: Evidence for selective lossof G(i) coupling
Autore:
Fuchs, S; Amiel, J; Claudel, S; Lyonnet, S; Corvol, P; Pinet, F;
Indirizzi:
Coll France, INSERM, U36, F-75005 Paris, France Coll France Paris FranceF-75005 nce, INSERM, U36, F-75005 Paris, France Hop Necker Enfants Malad, INSERM, U393, Paris, France Hop Necker Enfants Malad Paris France alad, INSERM, U393, Paris, France
Titolo Testata:
MOLECULAR MEDICINE
fascicolo: 2, volume: 7, anno: 2001,
pagine: 115 - 124
SICI:
1076-1551(200102)7:2<115:FCOTMO>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
SHAH-WAARDENBURG SYNDROME; ETB RECEPTOR; GERMLINE MUTATIONS; MISSENSE MUTATION; STRUCTURAL BASIS; NERVOUS-SYSTEM; CDNA; CLONING; RET; SUBTYPE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Pinet, F Coll France, INSERM, U36, 3 Rue Ulm, F-75005 Paris, France Coll France 3 Rue Ulm Paris France F-75005 F-75005 Paris, France
Citazione:
S. Fuchs et al., "Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease: Evidence for selective lossof G(i) coupling", MOL MED, 7(2), 2001, pp. 115-124

Abstract

Background: Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease. It leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified : RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or sporadic HSCR. Only few EDNRB mutations found in HSCR have been explored and some of them seem to be non fonctional variants. Materials and Methods: The properties of three mutant human endothelin B receptor (hET(B)) (G57S, R319W and P383L) in isolated HSCR were analyzed. Stable recombinant cells expressing the three mutants and the wild-type (WT) were established. The hET(B) receptors were characterized for I-125 ET-1 binding, ET-1 induced signaling : calcium transient, AP-1 transcriptional factor activation and cAMP accumulation. Results: Immunofluorescence experiments showed normal cellular distributions of the mutant G57S, R319W and WT hET(B) receptors. In contrast, the P383L hET(B) mutant receptor was concentrated near the nucleus and essentially no ET-1 binding was detected. The two other mutants (G57S and R319W) bound ET-1 normally, induced calcium transients and activated the AP-1 pathway inthe same way as wild type, but did not inhibit adenylate cyclase. The G57ShET(B) mutant even stimulated cAMP accumulation which was blocked by pertussis toxin. Conclusion The absence of the P383L mutant receptor from the membrane clearly indicates that this mutation could be involved in HSCR. The G57S and R319W mutant receptors, despite their normal coupling to G(alphaq) have a defect in the G(alphai) signaling pathway and the G57S mutation couples to G(alphas). These observations allow us to hypothesize that cAMP signaling might be involved in the differenciation of neural cells in the bowel.

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Documento generato il 04/04/20 alle ore 15:16:02