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

Nisar, Shaista P and Lordkipanidzé, Marie and Jones, Matthew L and Dawood, Ban and Murden, Sherina and Cunningham, Margaret R and Mumford, Andrew D and Wilde, Jonathan T and Watson, Steve P and Mundell, Stuart J and Lowe, Gillian C, UK GAPP Study Group (2014) A novel thromboxane A2 receptor N42S variant results in reduced surface expression and platelet dysfunction. Thrombosis and haemostasis, 111 (5). pp. 923-932. ISSN 0340-6245

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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.


Nisar, Shaista P, Lordkipanidzé, Marie, Jones, Matthew L, Dawood, Ban, Murden, Sherina, Cunningham, Margaret R ORCID logoORCID: https://orcid.org/0000-0001-6454-8671, Mumford, Andrew D, Wilde, Jonathan T, Watson, Steve P, Mundell, Stuart J and Lowe, Gillian C;