A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis

Abstract

We investigated the cause of mild mucocutaneous bleeding in a 14-year-old male patient (P1). Platelet aggregation and ATP secretion induced by arachidonic acid and the thromboxane A 2 receptor (TxA 2 R) agonist U46619 were reduced in P1 compared with controls, whereas the responses to other platelet agonists were

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

“…This interaction causes a wide variety of biological effects, including platelet aggregation. To this end, TPR's clear role in normal hemostasis is supported by the finding that “patients” have a bleeding disorder as a result of a point mutation in the receptor protein 14, 15, 16. On the other hand, upregulated signaling through TPR has been implicated in the pathogenesis of multiple cardiovascular and thrombosis‐based diseases 17, 18, 19, 20.…”

TBXA2R gene variants associated with bleeding

“…To date, one quantitative defect causing reduced TPα receptor expression (2) and four qualitative defects caused by TPα receptor amino acid substitutions have been reported ((6–9); see Table I and Figure 1). …”

“…The genotyping and phenotyping of platelets (GAPP) consortium has identified and characterized a series of rare variants in a number of platelet GPCR genes (13,14) including TBXA2R (Table I (6–8)). GAPP developed an approach for the rapid identification and characterization of rare genetic variations causing defects within platelet proteins (13).…”

“…One example was identified in a patient with a history of bruising and prolonged epistaxes since infancy (6). TPα receptor-stimulated platelet activity was reduced in the patient whereas other platelet receptor responses were similar to responses in healthy controls.…”

“…Why the Asp304Asn substitution causes such a significant decrease in ligand binding at the TPα receptor is unclear. Potentially, this substitution may have a loss of function effect that is unique to the TPα receptor, although it has been postulated that this residue may have a more complex role in stabilizing ligand binding pocket integrity (6). …”