1例遗传性蛋白S缺陷导致静脉血栓栓塞症分析

Analysis of a patient with inherited protein S deficiency causing venous thromboembolism

目的分析一例杂合缺失变异导致遗传性蛋白S(PS)缺陷症的临床特征及基因变异情况,探讨PS缺陷与静脉血栓栓塞的关系。方法选取1个遗传性蛋白S缺陷症家系为研究对象。检测先证者及其家系成员(2代5人)蛋白S水平及其他凝血指标。采用PCR法扩增PROS1基因所有外显子及侧翼序列等,并采用直接DNA测序及进行基因分析。使用计算机预测软件分析变异氨基酸位点的危害性及变异后对蛋白质功能的影响。结果基因分析显示先证者和其叔叔PROS1基因第5外显子均存在c.458_458delA杂合缺失变异,导致第153位的赖氨酸突变为丝氨酸并框移了6个氨基酸后产生终止密码子(p.Lys153Serfs^(*)6)。Mutation Taster软件预示该缺失变异为有害变异,能够引起相应的疾病;蛋白质模型分析显示该缺失变异导致其与周围氨基酸的氢键发生了改变,所产生的截短蛋白功能不全,可能致使蛋白质错误折叠或无义介导的RNA衰变。结论PROS1第5外显子存在c.458_458delA(p.Lys153Serfs^(*)6)杂合缺失变异是先证者发生静脉血栓栓塞的诱因之一。

Objective To analyze the clinical features and gene variants of a family with hereditary protein S(PS)deficiency caused by a heterozygous PROS1 gene variant and to investigate the association between PS deficiency and venous thromboembolism.Methods A family with inherited PS deficiency was recruited.The PS levels and other coagulation parameters of the proband and family members(5 individuals in 2 generations)were measured.Using the PCR to amplify the 15exons and flanking regions of the PROS1 gene.Then the PCR products were directly sequenced.Using the online prediction software to analyze the deleterious and the effect on protein function before and after the variation.Results Two family members were diagnosed with hereditary PS deficiency.Genetic analysis showed that the proband and his uncle has carried a heterozygous deletion variant of c.458_458delA in exon 5 of PROS1 gene,which resulted in a p.Lys153Serfs^(*)6 variant.Mutation Taster indicated that this was a harmful variant.The protein model showed that this variant changed the hydrogen bonds surrounding p.Lys153 and produced a defective truncated protein,resulting in nonsense-mediated RNA decay and leading to missing fold of PS protein.Conclusion The c.458_458delA(p.Lys153Serfs^(*)6)heterozygous deletion variant of PROS1 gene was identified as one of predisposing factor for venous thromboembolism in the proband.