遗传性蛋白S缺陷症一家系调查  

Hereditary protein S deficiency:survey results from a Chinese pedigree

作　　者：李泽亚 张丽萍[1] 李博[1] 张鹏[2] 王美娜 王冠群 张尉华[1] Li Zeya;Zhang Liping;Li Bo;Zhang Peng;Wang Meina;Wang Guanqun;Zhang Weihua(Department of Cardiology,First Hospital of Jilin University,Changchun 130021,China;Department of Genetic Diagnosis Center,First Hospital of Jilin University,Changchun 130021,China;Department of Cardiology,Third Shandong Provincial,Jinan 250031,China)

机构地区：[1]吉林大学第一医院心血管内科,长春130021 [2]吉林大学第一医院基因诊断中心,长春130021 [3]山东省立第三医院心血管内科,济南250031

出　　处：《中华心血管病杂志》2020年第10期831-836,共6页Chinese Journal of Cardiology

基　　金：吉林省教育厅“十三五”科学技术项目(JJKH20190001KJ)。

摘　　要：目的:调查一遗传性蛋白S缺陷症家系的临床特征及基因突变情况,并分析其基因型与表型的关系。方法:该研究为一家系调查。先证者自2016年1月多次就诊于吉林大学第一医院,调查包括诊断为遗传性蛋白S缺陷症的先证者及其家系成员共26名。收集该家系成员的临床资料并留取血样本。采用外显子高通量测序技术对家系成员行基因筛查,并利用Sanger测序对发现的突变位点进行验证。利用蛋白质功能预测软件SIFT、PolyPhen_2、nsSNPAnalyzer、MutPred2进行基因突变致病性预测。使用Swiss-Model在线同源建模软件对蛋白S野生型及突变型进行蛋白三级结构的同源建模,观察基因突变对蛋白三级结构的影响。结果:该家系中4代共26名直系亲属中有4人临床诊断为遗传性蛋白S缺陷症,先证者表现为反复肺栓塞及下肢静脉血栓,其舅舅及母亲有下肢静脉血栓病史,余家系成员无血栓/栓塞病史。测序发现先证者及部分家系成员(Ⅱ2、Ⅱ6、Ⅲ4、Ⅳ2)的PROS1基因第2号外显子存在c.200A>C基因突变。SIFT、PolyPhen_2、nsSNPAnalyzer、MutPred2对该基因突变的预测结果均为有害。Swiss-Model同源建模结果显示,基因突变后第67位氨基酸由谷氨酸突变为丙氨酸。结论:该遗传性蛋白S缺陷症家系携带c.200A>C基因突变,该突变可能引起蛋白S活性降低,从而导致患者反复下肢静脉血栓及肺栓塞。Objective To investigate the clinical characteristics and gene mutation,and analyze the association between genotype and phenotype of hereditary protein S deficiency in a Chinese pedigree.Methods Hereditary protein S deficiency was diagnosed in January 2016 in our hospital.A total of 26 family members were surveyed in this study.Blood samples and clinical data were collected from them,and mutations were identified by Sanger sequencing.Pathogenicity of gene mutations was predicted by protein function prediction software including SIFT,PolyPhen_2,nsSNPAnalyzer and MutPred2.Swiss Model(https://swissmodel.expasy.org/)was used to perform homology modeling of the tertiary structure of the protein S wild-type and mutant-type,and observe the impact of gene mutation on the tertiary structure of the protein.Results Four out of 26 family members of 4 generations were clinically diagnosed with hereditary protein S deficiency.The proband presented with recurrent pulmonary embolism and venous thromboembolism of the lower extremities,and her uncle and mother had a history of venous thromboembolism.Sequencing revealed a mutation in the c.200A>C gene in the second exon of the PROS1 gene of proband and part of her families(Ⅱ2,Ⅱ6,Ⅲ4,Ⅳ2).The prediction results of this gene mutation performed by SIFT,PolyPhen_2,nsSNPAnalyzer,MutPred2 were all harmful.The results of Swiss-Model homology modeling showed that the 67th amino acid was mutated from glutamic acid to alanine because of this gene mutation.Conclusion A gene mutation cDNA(c.200A>T)is identified in a Chinese pedigree with hereditary protein S deficiency.This gene mutation may reduce protein S activity,which may cause recurrent pulmonary embolism and venous thromboembolism of the patients.

关 键 词：肺栓塞 遗传性蛋白S缺陷症 

分 类 号：R596[医药卫生—内科学]