PDF(Pubmed)
Abstract：
Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe-moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules.
摘要：
凝血基因中的遗传性缺陷基本上表达了与候选前导基因的突变等位基因数量直接相关的临床表型的严重程度（例如，杂合子vs.纯合子）和可能的其他共同遗传性状。F5基因,编码凝血因子V(FV)，在凝血级联中起着双面作用，表现出促凝血和抗凝血功能。因此，该基因的缺陷可能会导致出血或血栓形成。Sanger序列分析检测到F5基因外显子13中的过早终止密码子（c.3481C>T;p.R1161Ter）在一个家族的几个成员中，其特征是循环FV水平低，临床表型相反。提案，一名29岁的男性，受到复发性出血的影响，对于F5终止密码子和F5c.1691G>A（p。R506Q；FV-Leiden）遗传自杂合子父母，这暗示着组合的顺式隔离。终止密码子的纯合状态完全消除了F5基因的表达（FV：Ag<1％；FV：C<1％；分别通过ELISA和基于PT的一阶段凝血测定进行评估），移除,反过来,FV-Leiden有可能成为血栓前分子.他的父亲（57岁），以严重复发性静脉血栓形成为特征，接受了完整的分子血栓筛查,揭示杂合F2G20210A缺陷，而他的母亲（56y.o.），对进一步的常见凝血缺陷呈阴性，报告完全无症状的回忆。为了剖析这些相互矛盾的表型，我们进行了ProC®Global（SiemensHelthineers）凝血测试，旨在评估每个家庭成员的全球促凝剂和抗凝剂平衡，通过APC敏感性比（APC-sr）研究对活化蛋白C（APC）的反应。该提案对APC的反应出乎意料地差（APC-sr：1.09；n.v.>2.25），父亲和母亲的APC-sr分别为1.5和2.0。尽管ProC®Global普遍检测到FV的抗凝侧，推测异常低的APC-sr及其不一致的重度-中度出血表型可能提示突变FVp.506QQ通过自然连读或可能的可变剪接机制残留表达.凝血途径可以通过自然和诱导策略进行生理再平衡。所描述的见解可能能够追踪新的治疗方法和重新平衡分子的设计。
