Human Thromboxane A2 Receptor Genetic Variants: In Silico, In Vitro and -In Platelet- AnalysisReportar como inadecuado

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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 C68S, V80E, E94V, A160T, V176E, and V217I 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 C68S to normal V217I, with most variants demonstrating functional alteration in binding, expression or activation V80E, E94V, A160T, and V176E. 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.

Autor: Scott Gleim, Jeremiah Stitham, Wai Ho Tang, Hong Li, Karen Douville, Prashen Chelikani, Jeffrey J.Rade, Kathleen A. Martin, John



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