A novel thromboxane A2 receptor N42S variant results in reduced surface expression and platelet dysfunction

Research output: Contribution to journalArticlepeer-review


  • S. P. Nisar
  • Matthew Jones
  • S. Murden
  • Margaret R. Cunningham
  • A. D. Mumford
  • J. T. Wilde
  • S. J. Mundell

Colleges, School and Institutes


A small number of thromboxane receptor variants have been described in patients with a bleeding history that result in platelet dysfunction. We have identified a patient with a history of significant bleeding, who expresses a novel heterozygous thromboxane receptor variant that predicts an asparagine to serine substitution (N42S). This asparagine is conserved across all class A GPCRs, suggesting a vital role for receptor structure and function.We investigated the functional consequences of the TP receptor heterozygous N42S substitution by performing platelet function studies on platelet-rich plasma taken from the patient and healthy controls. We investigated the N42S mutation by expressing the wild-type (WT) and mutant receptor in human embryonic kidney (HEK) cells. Aggregation studies showed an ablation of arachidonic acid responses in the patient, whilst there was right-ward shift of the U46619 concentration response curve (CRC). Thromboxane generation was unaffected. Calcium mobilisation studies in cells lines showed a rightward shift of the U46619 CRC in N42S-expressing cells compared to WT. Radioligand binding studies revealed a reduction in BMax in platelets taken from the patient and in N42S-expressing cells, whilst cell studies confirmed poor surface expression. We have identified a novel thromboxane receptor variant, N42S, which results in platelet dysfunction due to reduced surface expression. It is associated with a significant bleeding history in the patient in whom it was identified. This is the first description of a naturally occurring variant that results in the substitution of this highly conserved residue and confirms the importance of this residue for correct GPCR function.


Original languageEnglish
Pages (from-to)923-932
JournalThrombosis and Haemostasis
Issue number5
Early online date23 Jan 2014
Publication statusPublished - May 2014


  • receptors, acquired, gene mutations , platelet pharmacology, inherited/acquired platelet disorders, platelet pathology/inherited