Abstract
Antithrombin III (AT) is the main inhibitor of blood coagulation proteases like thrombin and factor Xa. In this study we report the identification and characterization of several variants of AT for the first time in Indian population. We screened 1950 deep vein thrombosis (DVT) patients for AT activity and antigen levels. DNA sequencing was further carried out in patients with low AT activity and/or antigen levels to identify variations in the AT gene. Two families, one with type I and the other with type II AT deficiency were identified. Three members of family I showed an increase in the coagulation rates and recurrent thrombosis in this family was solely attributed to the rs2227589 polymorphism. Four members of family II spanning two generations had normal antigen levels and decreased AT activity. A novel single nucleotide insertion, g.13362_13363insA in this family in addition to g.2603T>C (p.R47C) mutation were identified. AT purified from patient’s plasma on hi-trap heparin column showed a marked decrease in heparin affinity and thrombin inhibition rates. Western blot analysis showed the presence of aggregated AT. We also report a novel point mutation at position g.7549 A>G (p.T280A), that is highly conserved in serpin family. Variant protein isolated from patient plasma indicated loss of regulatory function due to in-vivo polymerization. In conclusion this is the first report of AT mutations in SERPINC1 gene in Indo-Aryan population where a novel point mutation p.T280A and a novel single nucleotide insertion g.13362_13363insA are reported in addition to known variants like p.R47C, p.C4-X and polymorphisms of rs2227598, PstI and DdeI.
Highlights
Thrombosis is a complex disease associated with most of the vascular disorders including myocardial infraction, cerebrovascular & peripheral arterial diseases and deep vein thrombosis (DVT)
In addition to more than 250 mutations that are known in the Antithrombin III (AT) gene rs2227589 polymorphism has been consistently shown to be associated with slightly lower levels of AT activity and plasma antigen levels [17]
It was performed on 3 large case control studies, LETS (443 cases and 453 controls; OR: 1.42; p-value: 0.03), MEGA-1 (1398 cases and 1757 controls; OR: 1.24; p-value: 0.01) and MEGA-2 (1314 cases and 2877 controls; OR: 1.29; p-value:
Summary
Thrombosis is a complex disease associated with most of the vascular disorders including myocardial infraction, cerebrovascular & peripheral arterial diseases and deep vein thrombosis (DVT). Any inadvertent clotting either due to mutation of procoagulant or anticoagulant factors or due to acquired factors may lead to life threatening thromboembolic disorders. AT has evolved a complex heparin induced conformational change mechanism to efficiently inhibit these proteases. This has made AT prone to structural and functional defects [4]. In addition to point mutations, rs2227589 polymorphism located at 140bp downstream of exon 1 in the AT gene has been shown to be associated with a high risk of thrombosis. In a study conducted by Bezemer et al on 19682 SNPs located in 10887 genes, rs2227589 was found to be one of the three polymorphisms associated with a high risk of DVT [11]
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