A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function
A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function
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DOI：
10.1182/blood-2014-08-592733
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发表时间：
2015-03-12
期刊：
影响因子：
20.3
通讯作者：
Middeldorp, Saskia
中科院分区：
文献类型：
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作者：
Cunha, Marisa L. R.;Bakhtiari, Kamran;Middeldorp, Saskia
我们调查了一个荷兰小家庭的出血素质，延长凝血酶原时间，活化部分凝血活酶时间，在其中没有分类诊断。2名受影响亲属的体外凝血酶生成严重减少，组织因子途径抑制物（TFPI）水平显著升高。为了确定出血素质的遗传原因，我们对所有在世亲属进行了全外显子组测序分析。我们在F5基因中发现了一种新的功能获得性突变（c.C2588G），该突变导致F5的异常剪接，并最终导致短因子V蛋白（从B结构域缺失623个氨基酸），我们称之为因子V阿姆斯特丹。阿姆斯特丹因子V与TFPI结合，延长其半衰期和浓度。这是第二份关于短型凝血因子V与TFPI水平升高之间相关性的报告，导致凝血酶生成严重减少和出血倾向。
We investigated a small Dutch family with a bleeding diathesis, prolonged prothrombin, and activated partial thromboplastin times, in whom no classifying diagnosis was made. The 2 affected relatives had severely decreased in vitro thrombin generation, and levels of tissue factor pathway inhibitor (TFPI) were strongly increased. To identify the genetic cause of the bleeding diathesis, we performed whole exome sequencing analysis of all living relatives. We found a novel gain-of-function mutation in the F5 gene (c.C2588G), which leads to an aberrant splicing of F5 and ultimately to a short factor V protein (missing 623 amino acids from the B domain), which we called factor V Amsterdam. Factor V Amsterdam binds to TFPI, prolonging its half-life and concentration. This is the second report of an association between a shorter form of factor V and increased TFPI levels, resulting in severely reduced thrombin generation and a bleeding tendency.