Variants like AT Murcia (K241E) causing altered glycosylation pattern, AT Rouen-IV & AT London (R24C) that leads to abolition and reduction in inhibitory activity, or those like F229L causing spontaneous in vivo polymerization have provided valuable insight into the underlying mechanism of AT deficiency. AT deficiency may be either type I, where both the activity and antigen levels in the plasma are reduced or type II, where normal antigen levels are associated with a reduced AT activity level. The first mutation linked to AT deficiency was characterized in 1983. AT gene (SERPINC1) spans 13.4kb of genomic DNA and is located on chromosome 1q23-25. However this has also made AT prone to structural and functional defects. AT has evolved a complex heparin induced conformational change mechanism to efficiently inhibit these proteases. AT regulates coagulation by inhibiting thrombin, factors IX, Xa and XI of the blood coagulation system. The significance of AT in hemostasis is evident by the fact that its heterozygous deficiency is associated with increased risk of thrombosis whereas homozygous deficiency might be fatal. IntroductionĪntithrombin III (AT), a member of serpin ( serine proteinase inhibitor) super-family is the most important endogenous anticoagulant. 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. Variant protein isolated from patient plasma indicated loss of regulatory function due to in-vivo polymerization. We also report a novel point mutation at position g.7549 A>G (p.T280A), that is highly conserved in serpin family. Western blot analysis showed the presence of aggregated AT. AT purified from patient’s plasma on hi-trap heparin column showed a marked decrease in heparin affinity and thrombin inhibition rates. A novel single nucleotide insertion, g.13362_13363insA in this family in addition to g.2603T>C (p.R47C) mutation were identified. Four members of family II spanning two generations had normal antigen levels and decreased AT activity. 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. Two families, one with type I and the other with type II AT deficiency were identified. DNA sequencing was further carried out in patients with low AT activity and/or antigen levels to identify variations in the AT gene. We screened 1950 deep vein thrombosis (DVT) patients for AT activity and antigen levels. In this study we report the identification and characterization of several variants of AT for the first time in Indian population.
Antithrombin III (AT) is the main inhibitor of blood coagulation proteases like thrombin and factor Xa.
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