Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis
Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis
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DOI：
10.1016/j.thromres.2008.08.020
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发表时间：
2009-05-01
影响因子：
7.5
通讯作者：
Ikedai, Yasuo
中科院分区：
文献类型：
--
作者：
Miyata, Toshiyuki;Sato, Yukiko;Ikedai, Yasuo
简介：PROS1、PROC 和 SERPINC1（抗凝血酶）的遗传缺陷是深静脉血栓 (DVT) 的危险因素。由于表型变异，这三个基因的遗传缺陷的诊断有时很困难。本研究旨在揭示日本 DVT 患者中这三个基因的非同义突变频率。 患者/方法：疑难病症对策研究组的凝血异常亚组登记了 173 名 DVT 患者。我们对所有 DNA 样本中三个基因的整个编码区进行了测序，并鉴定了非同义突变。结果和结论：对于 PROS1，我们在 28 名 DVT 患者中发现了 15 个非同义突变；对于PROC，17名患者中有10个非同义突变；对于 SERPINC1，14 名患者中有 13 个非同义突变。 5名患者存在PROS1和PROC两种突变，且全部存在PROS1 K196E突变。我们之前发现了一名患有大量 PROS1 基因缺失的患者。因此，173 名患者中有 55 名 (32%) 在这三种基因中携带至少一种遗传缺陷。在 15 名日本 DVT 患者中发现的 PROS1 K196E 突变是最常见的，其次是 PROC K193del 和 V339M 突变，各在 4 名患者中发现。我们的数据表明，PROC K193del 突变导致抗凝血活性丧失，但不导致酰胺分解活性丧失。我们的努力是第一个 DNA 重测序研究，旨在识别 DVT 患者的遗传变异，而不考虑他们的血浆活性和抗原。为了最大限度地减少未来评估遗传缺陷对 DVT 影响的选择偏差，我们必须连续招募患者。 (C) 2008 Elsevier Ltd. 保留所有权利。
Introduction: Genetic deficiencies of PROS1, PROC, and SERPINC1 (antithrombin) are risk factors for deep vein thrombosis (DVT). Diagnosis of the inherited deficiencies of these three genes is sometimes difficult because of the phenotypic variability. This study was undertaken to reveal the frequency of nonsynonymous mutations of these three genes in Japanese DVT patients.Patients/Methods: One hundred seventy-three DVT patients were registered by the Sub-group of Blood Coagulation Abnormality, from the Study Group of Research on Measures for Intractable Diseases. We sequenced the entire coding regions of the three genes in all DNA samples and identified the nonsynonymous mutations. Results and Conclusions: For PROS1 we identified 15 nonsynonymous mutations in 28 DVT patients; for PROC, 10 nonsynonymous mutations in 17 patients; and for SERPINC1, 13 nonsynonymous mutations in 14 patients. Five patients had two mutations in PROS1 and PROC, and all of them had PROS1 K196E mutation. We previously identified one patient with a large PROS1 gene deletion. Thus, 55 out of 173 patients (32%) carried at least one genetic defect in the three genes. The PROS1 K196E mutation found in 15 Japanese DVT patients was the most prevalent Mutations of PROC K193del and V339M were the second, each found in four patients. Our data suggested that the PROC K193del mutation caused the loss of the anticoagulant activity but not the amidolytic activity. Our effort is the first DNA resequencing study to identify the genetic variations in DVT patients without any consideration of their plasma activities and antigens. To minimize selection bias in a future evaluation of the contribution of genetic deficiency to DVT, we must recruit patients consecutively. (C) 2008 Elsevier Ltd. All rights reserved.