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

Shaista P Nisar, Marie Lordkipanidzé, Matthew L Jones, Ban Dawood, Sherina Murden, Margaret R Cunningham, Andrew D Mumford, Jonathan T Wilde, Steve P Watson, Stuart J Mundell, Gillian C Lowe, UK GAPP Study Group

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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
Number of pages10
JournalThrombosis and haemostasis
Issue number5
Early online date23 Jan 2014
Publication statusPublished - 5 May 2014


  • receptors
  • gene mutations
  • platelet pharmacology
  • platelet disorders
  • platelet pathology

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