Platelet dysfunction associated with the novel Trp29Cys thromboxane A2 receptor variant

Mumford, Andrew D; Nisar, Shaista P.; Darnige, Luc; Jones, Matthew L.; Bachelot‐Loza, Christilla; Gandrille, Sophie; Zinzindohoué, Franck; Am, Fischer; Mundell, Stuart J; Gaussem, Pascale

doi:10.1111/jth.12117

Cited by 25 publications

(23 citation statements)

References 28 publications

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“…For example, it can be used to resolve IPDs with digenic roots as illustrated by observations in TBXA2R: 4 reports describe LOF variants of TBXA2R in patients with platelet defects as a dominant finding. 78,[116][117][118] Although heterozygosity for the TBXA2R variants correlated with the platelet defect in these carriers, there was no association with bleeding problems. It was noted that a potential second genetic factor would be required to cause bleeding.…”

Section: Protein-protein Interaction Networkmentioning

confidence: 85%

Inherited platelet disorders: toward DNA-based diagnosis

Lentaigne

Freson

Laffan

et al. 2016

Blood

119

101

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Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

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Section: Protein-protein Interaction Networkmentioning

confidence: 85%

Inherited platelet disorders: toward DNA-based diagnosis

Lentaigne

Freson

Laffan

et al. 2016

Blood

119

101

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Alshbool

Karim

Espinosa

et al. 2018

JAHA

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BackgroundDespite the well‐established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand‐binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR‐based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity.Methods and ResultsWe used a mouse keyhole limpet hemocyanin/peptide‐based vaccination approach rationalized over the TPR ligand‐binding domain (ie, the C‐terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C‐terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C‐terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb‐IIIa); (3) selectively inhibited TPR‐mediated platelet aggregation, platelet‐leukocyte aggregation, integrin glycoprotein IIb‐IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis.ConclusionsCollectively, our findings shed light on TPR's structural biological features, and demonstrate that the C‐terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine‐based approach that should have therapeutic applications.

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“…Two further function-disrupting TBXA2R variants predicting amino acid substitutions within TMD1 have also been characterized (Figure 1; (7,8)). Both of these variations reduce TPα receptor expression at the cell surface, suggesting an important role for TMD1 in the regulation of anterograde receptor traffic.…”

mentioning

confidence: 99%

“…Both of these variations reduce TPα receptor expression at the cell surface, suggesting an important role for TMD1 in the regulation of anterograde receptor traffic. The first of these variants, a Trp29Cys substitution, was identified in a patient with abnormal postsurgical bleeding and reduced TPα receptor-mediated platelet activation responses (7). Ligand-binding studies indicated a reduction in both surface receptor expression and ligand-binding affinity with the Trp29Cys variant.…”

mentioning

confidence: 99%

“…Notably, the presence of heterozygous variants in TBXA2R and other GPCR genes does not always correlate with a clinical bleeding phenotype, even though they are consistently associated with abnormal platelet functional responses in diagnostic laboratory tests. For example, although the pedigree index cases with heterozygous variants predicting the Asp304Asn and Trp29Cys TPα receptor substitutions presented with mild bleeding, pedigree members who were also heterozygous for these variants were asymptomatic (6,7). One explanation is that heterozygous loss of function TBXA2 variants are insufficient alone to cause a clinical bleeding phenotype, but require other mild hemostatic defects in affected patients to manifest as bleeding (21).…”

mentioning

confidence: 99%

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TBXA2R gene variants associated with bleeding

Mundell

Mumford

2018

Platelets

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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.

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Platelet dysfunction associated with the novel Trp29Cys thromboxane A2 receptor variant

Abstract: sem P, The UK GAPP Study Group. Platelet dysfunction associated with the novel Trp29Cys thromboxane A 2 receptor variant. J Thromb Haemost 2013; 11: 547-554. Summary

Cited by 25 publications

References 28 publications

Inherited platelet disorders: toward DNA-based diagnosis

Inherited platelet disorders: toward DNA-based diagnosis

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

TBXA2R gene variants associated with bleeding

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Platelet dysfunction associated with the novel Trp29Cys thromboxane A2 receptor variant

Abstract: sem P, The UK GAPP Study Group. Platelet dysfunction associated with the novel Trp29Cys thromboxane A 2 receptor variant. J Thromb Haemost 2013; 11: 547-554. Summary

Cited by 25 publications

References 28 publications

Inherited platelet disorders: toward DNA-based diagnosis

Inherited platelet disorders: toward DNA-based diagnosis

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

TBXA2R gene variants associated with bleeding

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Product

Resources

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