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PLoS One. 2013 Jun 28;8(6):e67314. doi: 10.1371/journal.pone.0067314. Print 2013.

Human thromboxane A2 receptor genetic variants: in silico, in vitro and "in platelet" analysis.

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1
Internal Medicine, Yale University School of Medicine, New Haven Connecticut, United States of America.

Erratum in

  • PLoS One. 2013;8(7). doi:10.1371/annotation/83ddfba7-3c48-4c96-8cd1-0f0b5f69a5d1.

Abstract

Thromboxane and its receptor have emerged as key players in modulating vascular thrombotic events. Thus, a dysfunctional hTP genetic variant may protect against (hypoactivity) or promote (hyperactivity) vascular events, based upon its activity on platelets. After extensive in silico analysis, six hTP-α variants were selected (C(68)S, V(80)E, E(94)V, A(160)T, V(176)E, and V(217)I) for detailed biochemical studies based on structural proximity to key regions involved in receptor function and in silico predictions. Variant biochemical profiles ranged from severe instability (C(68)S) to normal (V(217)I), with most variants demonstrating functional alteration in binding, expression or activation (V(80)E, E(94)V, A(160)T, and V(176)E). In the absence of patient platelet samples, we developed and validated a novel megakaryocyte based system to evaluate human platelet function in the presence of detected dysfunctional genetic variants. Interestingly, variant V80E exhibited reduced platelet activation whereas A160T demonstrated platelet hyperactivity. This report provides the most comprehensive in silico, in vitro and "in platelet" evaluation of hTP variants to date and highlightscurrent inherent problems in evaluating genetic variants, with possible solutions. The study additionally provides clinical relevance to characterized dysfunctional hTP variants.

PMID:
23840660
PMCID:
PMC3696120
DOI:
10.1371/journal.pone.0067314
[Indexed for MEDLINE]
Free PMC Article

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