Antithrombin III deficiency in Indian patients with deep vein thrombosis: identification of first India based AT variants including a novel point mutation (T280A) that leads to aggregation.
Antithrombin III deficiency in Indian patients with deep vein thrombosis: identification of first India based AT variants including a novel point mutation (T280A) that leads to aggregation.
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DOI：
10.1371/journal.pone.0121889
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jairajpuri MA
中科院分区：
文献类型：
--
作者：
Bhakuni T;Sharma A;Rashid Q;Kapil C;Saxena R;Mahapatra M;Jairajpuri MA
抗凝血酶 III (AT) 是凝血酶和 Xa 因子等凝血蛋白酶的主要抑制剂。在这项研究中，我们首次报告了印度人群中几种 AT 变体的鉴定和特征。我们对 1950 名深静脉血栓 (DVT) 患者进行了 AT 活性和抗原水平筛查。对 AT 活性和/或抗原水平低的患者进一步进行 DNA 测序，以鉴定 AT 基因的变异。确定了两个家族，一个为 I 型 AT 缺陷，另一个为 II 型 AT 缺陷。 I 家族的三名成员表现出凝血率增加，并且该家族中复发性血栓形成完全归因于 rs2227589 多态性。跨越两代的 II 家族的四名成员的抗原水平正常，但 AT 活性降低。除了 g.2603T>C (p.R47C) 突变之外，还鉴定出该家族中的新单核苷酸插入 g.13362_13363insA。在 hi-trap 肝素柱上从患者血浆中纯化的 AT 显示肝素亲和力和凝血酶抑制率显着降低。蛋白质印迹分析显示存在聚集的 AT。我们还报告了 g.7549 A>G (p.T280A) 位点的新点突变，该点突变在丝氨酸蛋白酶抑制剂家族中高度保守。从患者血浆中分离出的变异蛋白表明由于体内聚合而丧失了调节功能。总之，这是印度-雅利安人群 SERPINC1 基因 AT 突变的首次报告，其中除了 p.R47C、p.C4-X 等已知变体以及 rs2227598、PstI 和 DdeI 多态性之外，还报告了新的点突变 p.T280A 和新的单核苷酸插入 g.13362_13363insA。
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.
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DOI：
10.3324/haematol.2008.000604
发表时间：
2009-04-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Anton, Ana I.;Teruel, Raul;Sanchez-Vega, Beatriz
通讯作者：
Sanchez-Vega, Beatriz
影响因子：
2.9
作者：
Huntington, JA;Olson, ST;Gettins, PGW
通讯作者：
Gettins, PGW
DOI：
10.3324/haematol.2009.015487
发表时间：
2010-08-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Martinez-Martinez, Irene;Ordonez, Adriana;Corral, Javier
通讯作者：
Corral, Javier
影响因子：
10.4
作者：
Mushunje, A;Evans, G;Zhou, A
通讯作者：
Zhou, A
影响因子：
15.9
作者：
LANE, DA;OLDS, RJ;THEIN, SL
通讯作者：
THEIN, SL