Identification of the Novel G250R Variant Indicates a Role for Thrombomodulin in Modulating the Risk for Venous Thromboembolism

Abstract

Thrombomodulin displays anticoagulant properties through thrombin binding and protein C activation. In close relatives who had a history of recurrent VTE, a missense variant (G250R) in the EGF-1 domain was identified. In an asymptomatic 250R carrier, higher thrombin generation plasma values were found. Evaluation of cells transfected with the wild-type or the mutant construct using imaging technologies and flow cytometry provided evidences that the 250R variant significantly decreased protein localization on cell membrane. The different pattern of cell distribution suggested that the 250R variant is not able to sufficiently target the plasma membrane. Present findings add information to characterize protein structure-function relationships, further suggesting that misfolding of the protein modulates the expression of mature protein. Functional analyses of the 250R variant increase our understanding of the role of Thrombomodulin in coagulation and support the hypothesis that gene variants reducing protein functionality cause deficiency and behave as a thrombophilic risk factor.