3个家系遗传性抗凝血蛋白缺陷致血栓形成的基因分析

发布时间：2018-04-05 21:26

本文选题：抗凝蛋白缺陷　切入点：血栓形成　出处：《广西医科大学》2017年硕士论文

【摘要】：目的研究3个遗传性抗凝血蛋白缺陷致血栓形成家系临床表型及基因突变。方法收集抗凝血蛋白缺陷致血栓形成家系病史资料,分析患者及其家族成员的临床表现及辅助检查结果。采集先证者及其家族成员血样5ml置入1:9枸橼酸钠抗凝管中,采用发光底物法对先证者和家族成员进行蛋白C(PROC)活性、蛋白S(PROS)活性、抗凝血酶(AT)III活性进行测定;乙二胺四乙酸抗凝外周血提取基因组DNA,采用DNA直接测序法对先证者PROC、PROS1等相关基因进行基因检测。根据先证者的基因检测结果,对家族其他成员针对突变基因进行基因检测。结果家系一先证者(III-10)及其他3位家庭成员(II-5、II-6、III-9)、家系二先证者(II-3)及其他3位家庭成员(I-1、I-2、III-1)、家系三先证者(II-1)及其他1位无临床表现家庭成员(I-1)PROC基因第7外显子,c.565CT(编码区第565号核苷酸由胞嘧啶变异为胸腺嘧啶),导致氨基酸改变(第189号氨基酸由精氨酸变为色氨酸)。家系一先证者(III-10)诊断为“颅内静脉窦血栓形成”,父亲(II-5)表现为“下肢肿胀、疼痛”。家系二先证者(II-3)诊断为“颅内静脉窦血栓形成”,父亲(I-1)诊断为“左下肢深静脉血栓形成”。此外,家系一先证者(III-10)及6位家庭成员(II-5、II-7、II-9、II-10、III-9、III-15)的PROS1基因还发现两种突变,分别为(C-A)+520 to termination,导致氨基酸改变和c.2001AG(没有氨基酸替代)。其中,家系一成员(III-15)被诊断为“乆静脉血栓形成”。结论本次研究发现在三个家系中存在PROC基因第7外显子,c.565CT突变。它可能是导致3个家系先证者蛋白C活性下降及静脉血栓形成的主要原因。本研究在国内外首次报道了纯合子PROC(c.565CT)突变致青年缺血性卒中的病例。家系一中还发现PROS1基因(C-A)+520 to termination和c.2001AG突变,这两种突变可能会对蛋白S活性水平有影响,从而增加血栓形成的风险。
[Abstract]:Objective to study the clinical phenotype and gene mutation in three families with hereditary anticoagulant protein deficiency.Methods the family history of thrombus caused by anticoagulant protein deficiency was collected and the clinical manifestations and auxiliary examination results of the patients and their family members were analyzed.The blood samples of probands and their family members were collected and placed into the 1:9 sodium citrate anticoagulant tube. The activity of protein Cnprocr, protein SfP, and the activity of antithrombin titer III were determined by luminescent substrate method.The genomic DNA was extracted from the peripheral blood of ethylenediamine tetraacetic acid anticoagulant, and the genes related to proctrin PROS1 and other genes were detected by DNA direct sequencing.Based on the results of the proband gene test, the other members of the family were tested for the mutant gene.Nucleotides 565 mutated from cytosine to thymine, resulting in changes in amino acids (amino acid 189 from arginine to tryptophan)."Intracranial venous sinus thrombosis" was diagnosed as "intracranial venous sinus thrombosis", and "swelling and pain in lower extremities" was found in father's II-5.II-3 was diagnosed as "intracranial venous sinus thrombosis" and father as "deep venous thrombosis of left lower extremity".In addition, two mutations were found in the PROS1 gene of the first proband and six family members, I. e., II-5, II-7, II-9, II-10, III-9, and III-15, respectively, which were identified as C-A520 to terminations, leading to amino acid changes and c.2001AG1 (no amino acid substitution).Among them, a family member of the III-15) was diagnosed as "vein thrombosis."Conclusion in this study, the mutation of exon 7 of PROC gene was found on c. 565CT in three families.It may be the main cause of the decrease of protein C activity and venous thrombosis in three families.This study reported for the first time a case of ischemic stroke caused by homozygous procter c. 565CT2 mutation at home and abroad.Family 1 also found mutations in the PROS1 gene (C-A) 520 to termination and c.2001AG, which may have an effect on protein S activity, thus increasing the risk of thrombogenesis.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R596;R743.3

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