两个遗传性蛋白C缺陷症家系的临床特征与基因变异分析  

Clinical features and genotype analysis of two pedigrees with hereditary protein C deficiency

作　　者：陈荟琳 王胜[1] 杨婷[1] 洪姣 陈芳建 CHEN Huilin;WANG Sheng;YANG Ting;HONG Jiao;CHEN Fangjian(Department of Blood Transfusion,Quzhou Hospital Affiliated to Wenzhou Medical University(Ouzhou People’s Hospital),Quzhou 324000,China)

机构地区：[1]温州医科大学附属衢州医院(衢州市人民医院)输血科,浙江衢州324000

出　　处：《温州医科大学学报》2024年第10期811-816,共6页Journal of Wenzhou Medical University

基　　金：衢州市指导性科技攻关项目(2021044)。

摘　　要：目的:通过分析临床特征和基因变异情况,探讨两个遗传性蛋白C(PC)缺陷症家系与静脉血栓栓塞症(VTE)的关系。方法:回顾性分析2例PC缺陷患者的临床资料。采集2个先证者及各自家系成员(均3代共11人)外周静脉血,检测PC活性、蛋白S活性和抗凝血酶活性等凝血指标。采用PCR法扩增先证者的PROC基因所有外显子及侧翼序列并直接测序。通过软件分析,评估变异位点的保守性和致病性;构建蛋白模型,分析变异前后的空间结构。结果:先证者1临床表现为肺栓塞和下肢深静脉血栓形成(DVT),先证者2为DVT。基因分析显示,先证者1存在c.541T>G杂合错义变异和c.577-579del AAG杂合缺失变异;先证者2存在c.659G>A杂合错义变异。保守性和致病性分析证实,这些变异位点在同源物种氨基酸序列间大部分保守,并均为致病性变异;这些变异导致氨基酸间氢键及侧链基团的改变或产生截短蛋白。结论:c.541T>G杂合错义变异和c.577-579delAAG杂合缺失变异以及c.659G>A杂合错义变异分别与2个先证者PC水平下降有关,可能也是先证者出现VTE的原因之一。Objective:To investigate the clinical features and gene mutations in two families with hereditary protein C(PC)deficiency,and to explore the relationship between PC deficiency and vascular thromboembolism.Methods:Peripheral blood and clinical data were collected from two probands and their family members(eleven people across three generations),and the PC activity,protein S activity and antithrombin activity were detected to confirm the phenotypic diagnosis.PCR was used to amplify and directly sequence the PROC gene of the probands.Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci.Protein models were constructed to analyze the spatial structure before and after the mutation.Results:The clinical manifestations of proband 1 were pulmonary embolism and deep venous thrombosis of the lower extremities,and proband 2 had DVT.Genetic analysis revealed that the proband 1 had c.541T>G heterozygous missense mutation and c.577-579delAAG heterozygous deletion mutation and the proband 2 had a c.659G>A heterozygous missense mutation.Conservativeness and pathogenicity analysis confirmed that most of these amino acid residues were conserved,and all the mutations were found to be pathogenic.Protein models showed that most of these mutations caused changes in the hydrogen bonds between amino acids and side-chain groups or produced truncated proteins.Conclusion:The c.541T>G heterozygous missense mutation,c.577-579delAAG heterozygous deletion mutation and c.659G>A heterozygous missense mutation were related,respectively,to the decrease of PC level in these two probands,and these mutations may also be one of the reasons for the occurrence of VTE.

关 键 词：遗传性蛋白C缺陷症 静脉血栓栓塞症 杂合变异 蛋白C基因 

分 类 号：R394[医药卫生—医学遗传学]