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Cardiovascular Research 2003 60(3):518-528; doi:10.1016/j.cardiores.2003.09.015
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension

Cédric Blanpaina,b,1, Emmanuel Le Poulc, Jasmine Parmaa, Christiane Knoopd, Michel Detheuxc, Marc Parmentierb, Gilbert Vassarta,b,e and Marc J Abramowicz*,a,b,e

aService de Génétique Médicale, Université Libre de Bruxelles (ULB), 808 Lennik, B-1070 Brussels, Belgium
bIRIBHM, Université Libre de Bruxelles (ULB), 808 Lennik, B-1070 Brussels, Belgium
cEuroscreen S.A., Université Libre de Bruxelles (ULB), 808 Lennik, B-1070 Brussels, Belgium
dService de Pneumologie, Hôpital Erasme - ULB, Université Libre de Bruxelles (ULB), 808 Lennik, B-1070 Brussels, Belgium
eLaboratoire de Génétique Médicale, Université Libre de Bruxelles (ULB), 808 Lennik, B-1070 Brussels, Belgium

*Corresponding author. Service de Génétique Médicale, Hôpital Erasme, 808, Lennik St., B-1070 Brussels, Belgium. Tel.: +32-2-555-4145; fax: +32-2-555-4212. Email address: marcabra{at}ulb.ac.be

Objective: Appetite-suppressant drug fenfluramine is implicated in primary pulmonary hypertension (PPH) but the molecular pathways that mediate this effect are unknown. A mouse model incriminates the serotonin 5-HT2B receptor but contrasts with other models where this receptor has been shown to mediate pulmonary arterial relaxation via nitric oxide production. Methods: We analyzed the human 5-HT2B gene in 10 patients with appetite-suppressant drug-associated PPH. Results: A mutation causing premature truncation of the protein product was found in one patient. The mutation was not found in 80 control subjects and no 5-HT2B mutation was found in 18 PPH patients not associated with appetite-suppressants. Functional analysis of the transfected receptor expressed either transiently in COS cells or stably in CHO cells demonstrated that the mutated receptor fails to activate the second messenger inositol-phosphates cascade and subsequent intracellular calcium release, in spite of normal expression at the cell membrane. The mutated receptor had no constitutive activity, and produced no dominant negative effect on the wild-type receptor. Conclusion: Loss of serotonin 5-HT2B receptor function may predispose to fenfluramine-associated PPH in man.

KEYWORDS G-proteins; Pulmonary circulation; Receptors; Serotonin (5-HT); Human

1 Present address: Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York 10021-6399.

Time for primary review 31 days


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