Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension.
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-HT(2B) 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-HT(2B) 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-HT(2B) 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.


CONCLUSIONS
Loss of serotonin 5-HT(2B) receptor function may predispose to fenfluramine-associated PPH in man.
Blanpain
Cédric
C
Service de Génétique Médicale, Université Libre de Bruxelles, 808 Lennik, B-1070 Brussels, Belgium.
Le Poul
Emmanuel
E
Parma
Jasmine
J
Knoop
Christiane
C
Detheux
Michel
M
Parmentier
Marc
M
Vassart
Gilbert
G
Abramowicz
Marc J
MJ
D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects*; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004252:DNA Mutational Analysis; D005260:Female; D005277:Fenfluramine / Q000009:adverse effects*; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics* / Q000378:metabolism
D001067:Appetite Depressants; D044403:Receptor, Serotonin, 5-HT2B; D005277:Fenfluramine; D002118:Calcium