TBXA2R gene variants associated with bleeding

Abstract Platelet activity is regulated by a number of surface expressed G protein-coupled receptors (GPCRs) including the α isoform of the thromboxane receptor (TPα receptor). With the advance of genomic technologies, there has been a substantial increase in the identification of naturally occurring rare GPCR variants including in the TBXA2R gene, which encodes the TPα receptor. The study of patients with naturally occurring variants within TBXA2R associated with bleeding and abnormal TPα receptor function has provided a powerful insight in defining the critical role of TPα in thrombus formation. This review will highlight how the identification of these function-disrupting variants of the platelet TPα has contributed important structure-function information about these GPCRs. Further we discuss the potential implications these findings have for understanding the molecular basis of mild platelet based bleeding disorders.

[1]  X. Pillois,et al.  ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia , 2018, Platelets.

[2]  S. Mundell,et al.  Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding , 2018, Journal of thrombosis and haemostasis : JTH.

[3]  J. Hernández-Rivas,et al.  Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders , 2017, Haematologica.

[4]  S. Mundell,et al.  Impaired thromboxane receptor dimerization reduces signaling efficiency: A potential mechanism for reduced platelet function in vivo , 2017, Biochemical pharmacology.

[5]  S. Watson,et al.  Inherited platelet disorders: Insight from platelet genomics using next-generation sequencing , 2016, Platelets.

[6]  S. Mundell,et al.  Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking , 2016, Arteriosclerosis, thrombosis, and vascular biology.

[7]  S. Mundell,et al.  Diversity and Impact of Rare Variants in Genes Encoding the Platelet G Protein-Coupled Receptors , 2015, Thrombosis and Haemostasis.

[8]  S. Mundell,et al.  A novel thromboxane A2 receptor N42S variant results in reduced surface expression and platelet dysfunction , 2014, Thrombosis and Haemostasis.

[9]  K. Martin,et al.  Human Thromboxane A2 Receptor Genetic Variants: In Silico, In Vitro and “In Platelet” Analysis , 2013, PloS one.

[10]  S. Mundell,et al.  Platelet dysfunction associated with the novel Trp29Cys thromboxane A2 receptor variant , 2013, Journal of thrombosis and haemostasis : JTH.

[11]  Sai P. Pydi,et al.  New Insights into Structural Determinants for Prostanoid Thromboxane A2 Receptor- and Prostacyclin Receptor-G Protein Coupling , 2012, Molecular and Cellular Biology.

[12]  Harold J. Ting,et al.  Thromboxane A2 Receptor , 2012, Journal of cardiovascular pharmacology and therapeutics.

[13]  Á. Chamorro,et al.  Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial , 2011, The Lancet.

[14]  S. Honda,et al.  Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptor , 2011, Journal of thrombosis and haemostasis : JTH.

[15]  S. Mundell,et al.  A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis. , 2010, Blood.

[16]  S. Rasmussen,et al.  The structure and function of G-protein-coupled receptors , 2009, Nature.

[17]  M. Parenti,et al.  Mutational Analysis of the Highly Conserved ERY Motif of the Thromboxane A2 Receptor: Alternative Role in G Protein-Coupled Receptor Signaling , 2004, Molecular Pharmacology.

[18]  Y. Aizawa,et al.  Pathogenetic Analysis of Five Cases with a Platelet Disorder Characterized by the Absence of Thromboxane A2(TXA2)-Induced Platelet Aggregation in Spite of Normal TXA2 Binding Activity , 1996, Thrombosis and Haemostasis.

[19]  S. Narumiya,et al.  Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. , 1994, The Journal of clinical investigation.

[20]  S. Nakanishi,et al.  Cloning and expression of cDNA for a human thromboxane A2 receptor , 1991, Nature.

[21]  S. Mundell,et al.  Rare platelet G protein-coupled receptor variants : what can we learn? , 2015 .