Fidalgo Teresa, Martinho Patrícia, Salvado Ramon, Manco Licínio, Oliveira Ana C, Pinto Catarina S, Gonçalves Elsa, Marques Dalila, Sevivas Teresa, Martins Natália, Ribeiro Maria Letícia
Serviço de Hematologia Clínica, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
Eur J Haematol. 2015 Oct;95(4):294-307. doi: 10.1111/ejh.12488. Epub 2015 Mar 13.
Inherited protein C (PC) deficiency is a well-known risk factor for venous thrombosis (VT). Plasma PC levels are reliable in moderate to severe deficiencies; however, in mildly deficient individuals, the levels may overlap with those considered normal. Genetic studies of PROC, which encodes PC, could help identify carriers; genome-wide association studies (GWAS) have shown that approximately 50% of phenotypic variation in PC deficiency is caused by the cumulative effects of mutations in several other loci, namely in the PROCR.
With the main objective of determining the genotype/phenotype correlation in 59 Portuguese individuals from 26 unrelated families with history of thrombosis and repeatedly low/borderline PC plasma levels, we conducted a molecular study by direct sequencing of PROC; PROC promoter haplotypes and PROCR c.4600A>G polymorphism (rs867186), which are known to influence plasma PC concentrations, were also screened.
Twelve different PROC mutations were identified, one of them not previously reported, p.Cys105Arg. The mutation types and locations as well as haplotype combinations correlated with the phenotypic severity. The most frequent mutation, p.Arg199X, correlated with the CGTC haplotype and was identified in nine families containing patients with higher numbers of VT episodes. This mutation in homozygous individuals for the CGTC haplotype is a significant risk factor for VT in Portuguese.
These genetic family studies allowed the identification of the unknown carriers and individuals at a higher thrombotic risk within each family, thus permitting the evaluation of the need for prophylactic measures, particularly in at-risk situations.
遗传性蛋白C（PC）缺乏是静脉血栓形成（VT）的一个众所周知的危险因素。在中度至重度缺乏时，血浆PC水平是可靠的；然而，在轻度缺乏的个体中，其水平可能与正常水平重叠。对编码PC的PROC进行基因研究有助于识别携带者；全基因组关联研究（GWAS）表明，PC缺乏中约50%的表型变异是由其他几个基因座（即PROCR）突变的累积效应引起的。
为了确定来自26个无亲缘关系且有血栓形成病史以及反复出现低/临界PC血浆水平的葡萄牙家庭的59名个体的基因型/表型相关性，我们通过对PROC进行直接测序开展了一项分子研究；还筛查了已知会影响血浆PC浓度的PROC启动子单倍型和PROCR c.4600A>G多态性（rs867186）。
共鉴定出12种不同的PROC突变，其中一种p.Cys105Arg此前未被报道。突变类型、位置以及单倍型组合与表型严重程度相关。最常见的突变p.Arg199X与CGTC单倍型相关，在9个有更多VT发作患者的家庭中被发现。CGTC单倍型纯合个体中的这种突变是葡萄牙人VT的一个重要危险因素。
这些基因家族研究能够识别每个家庭中未知的携带者和血栓形成风险较高的个体，从而能够评估预防措施的必要性，特别是在高危情况下。
