Molecular basis of inherited antithrombin deficiency in Portuguese families: Identification of genetic alterations and screening for additional thrombotic risk factors
Molecular basis of inherited antithrombin deficiency in Portuguese families: Identification of genetic alterations and screening for additional thrombotic risk factors
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DOI：
10.1002/ajh.20067
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发表时间：
2004-06-01
影响因子：
12.8
通讯作者：
Crespo, F
中科院分区：
文献类型：
--
作者：
David, D;Ribeiro, S;Crespo, F
抗凝血酶（AT）是最重要的凝血丝氨酸蛋白酶抑制剂，在维持止血平衡中起重要作用。遗传性AT缺乏症，主要特征是易患复发性静脉血栓栓塞症，以常染色体显性遗传方式传播。在这项研究中，我们分析了潜在的遗传变异在12个无关的葡萄牙血栓性家族AT缺乏症。同时，还评估了FV Leiden突变、PT 20210 A、派-1 4G和MTHFR 677 T等位基因变体对AT缺陷患者血栓形成风险的调节作用。在6个无关的I型AT缺陷家系中发现了3个新的移码突变，即外显子4中的一个4-bp缺失和外显子6中的两个1-bp插入。一个新的错义突变外显子3a，改变了高度保守的F147残基，和一个新的剪接位点突变的不变受体AG二核苷酸的内含子2中也确定了无关的I型AT缺陷的家庭。除此之外，还鉴定了两个先前报道的改变AT反应位点键（R393-S394）并导致II-RS型缺陷的错义突变，以及先前报道的隐蔽剪接位点突变（IVS 4 - 14 G--> A）。在这些家族中，还观察到与FV Leiden突变和PAW 4G变体的共遗传相关的血栓形成风险增加。总之，我们目前的第一个数据有关的基础遗传变异在葡萄牙血栓性家族AT缺乏症，并确认FV莱顿突变，可能是PAW 4G变异代表额外的血栓形成的危险因素，在这些家庭。(C)2004 Wiley-Liss，Inc.
Antithrombin (AT), the most important coagulation serine proteases inhibitor, plays an important role in maintaining the hemostatic balance. Inherited AT deficiency, mainly characterized by predisposition to recurrent venous thromboembolism, is transmitted in an autosomal dominant manner. In this study, we analyzed the underlying genetic alterations in 12 unrelated Portuguese thrombophilic families with AT deficiency. At the same time, the modulating effect of the FV Leiden mutation, PT 20210A, PAI-1 4G, and MTHFR 677T allelic variants, on the thrombotic risk of AT deficient patients was also evaluated. Three novel frameshift alterations, a 4-bp deletion in exon 4 and two 1-bp insertions in exon 6, were identified in six unrelated type I AT deficient families. A novel missense mutation in exon 3a, which changes the highly conserved F147 residue, and a novel splice site mutation in the invariant acceptor AG dinucleotide of intron 2 were also identified in unrelated type I AT deficient families. In addition to these, two previously reported missense mutations changing the AT reactive site bond (R393-S394) and leading to type II-RS deficiency, and a previously reported cryptic splice site mutation (IVS4-14G --> A), were also identified. In these families, increased thrombotic risk associated with co-inheritance of the FV Leiden mutation and of the PAW 4G variant was also observed. In conclusion, we present the first data regarding the underlying genetic alterations in Portuguese thrombophilic families with AT deficiency, and confirm that the FV Leiden mutation and probably the PAW 4G variant represent additional thrombotic risk factors in these families. (C) 2004 Wiley-Liss, Inc.