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

Cédric Blanpain1, Emmanuel Le Poul, Jasmine Parma

  • 1Service de Génétique Médicale, Université Libre de Bruxelles, 808 Lennik, B-1070 Brussels, Belgium.

Cardiovascular Research
|December 9, 2003
PubMed
Abstract

Insights

Loss of serotonin 5-HT(2B) receptor function may predispose individuals to fenfluramine-associated primary pulmonary hypertension (PPH). This genetic defect impairs normal receptor signaling, potentially explaining the link between the appetite suppressant and PPH.

Area of Science:

  • Pharmacology
  • Genetics
  • Cardiovascular Medicine

Background:

  • Appetite suppressants like fenfluramine are linked to primary pulmonary hypertension (PPH).
  • The precise molecular mechanisms underlying fenfluramine-induced PPH remain unclear.
  • The serotonin 5-HT(2B) receptor's role in PPH is debated, with conflicting evidence regarding its function in pulmonary arteries.

Purpose of the Study:

  • To investigate the role of the serotonin 5-HT(2B) receptor in fenfluramine-associated primary pulmonary hypertension (PPH) in humans.
  • To identify potential genetic mutations in the 5-HT(2B) gene associated with PPH.

Main Methods:

  • Analysis of the human 5-HT(2B) gene in 10 patients with appetite-suppressant-associated PPH.
  • Genotyping of 80 control subjects and 18 PPH patients without appetite-suppressant association.
  • Functional assessment of mutated 5-HT(2B) receptors in transfected cell lines (COS and CHO cells).

Main Results:

  • A mutation causing premature protein truncation was identified in one patient with fenfluramine-associated PPH.
  • This specific mutation was absent in control subjects and PPH patients without drug association.
  • Functional studies revealed that the mutated 5-HT(2B) receptor failed to activate downstream signaling pathways (inositol phosphates and calcium release) despite normal cell membrane expression.

Conclusions:

  • Loss of serotonin 5-HT(2B) receptor function may increase susceptibility to fenfluramine-associated PPH in humans.
  • The identified mutation disrupts normal receptor signaling, providing a potential molecular explanation for the drug's adverse effect.
  • Further research is warranted to fully elucidate the 5-HT(2B) receptor's role in pulmonary vascular disease.

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