遗传性蛋白S缺陷症导致颅内静脉窦血栓形成分析  

Analysis of cerebral venous sinus thrombosis due to inherited protein S deficiency

作　　者：侯玲玲 徐斐[1] 谢海啸[1] 张柯 金艳慧[1] 王明山[1] 杨丽红[1] Hou Lingling;Xu Fei;Xie Haixiao;Zhang Ke;Jin Yanhui;Wang Mingshan;Yang Lihong(Department of Laboratory Medicine,the First Affiliated Hospital of Wenzhou Medical University,Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province,Wenzhou 325000,China)

机构地区：[1]温州医科大学附属第一医院检验科、浙江省检验诊断与转化研究重点实验室,温州325000

出　　处：《中华神经科杂志》2024年第11期1247-1253,共7页Chinese Journal of Neurology

基　　金：温州市基础性医疗卫生科技项目(Y20210111);浙江省检验诊断及转化研究重点实验室(2022E10022)。

摘　　要：目的对2个无义突变导致的遗传性蛋白S缺陷症(PSD)家系的表型与基因突变特点进行分析,探讨遗传性PSD与颅内静脉窦血栓形成(CVST)之间的关系。方法回顾性分析2023年7月、10月在温州医科大学附属第一医院神经内科确诊的2例CVST患者的临床及影像学资料,采集先证者1及其家系成员(2代3人)、先证者2及其家系成员(3代8人)的外周血标本,检测其蛋白S活性(PS:A),并对血浆总蛋白S抗原(TPS:Ag)、游离蛋白S抗原(FPS:Ag)等指标进行分析。扩增蛋白S基因(PROS1)所有15个外显子及其5′和3′的侧翼区,采用直接测序法分析其扩增产物,对测序结果使用Chromas软件与参考序列进行比对,寻找突变位点。结果先证者1为女性,先证者2为男性,均为中青年起病,临床均表现为CVST。先证者1的PS:A降低至29%,其母亲降低至35%;先证者2及其6名家庭成员的PS:A降低至21%~27%。2例先证者及其上述家系成员的TPS:Ag和FPS:Ag均同比例下降,初步诊断为Ⅰ型PSD。通过基因分析发现,先证者1及其母亲的PROS1基因第14号外显子存在c.1680T>A(p.Tyr560*)杂合无义突变;先证者2及其6位家系成员PROS1基因第14号外显子存在c.1687C>T(p.Gln563*)杂合无义突变。结论PSD患者及其家系成员的蛋白S水平降低可能与PROS1基因p.Tyr560*和p.Gln563*的无义突变有关,PSD患者出现CVST的临床表现也可能与这2种无义突变有关。ObjectiveTo investigate the relationship between inherited protein S deficiency(PSD)and cerebral venous sinus thrombosis(CVST)by phenotype and gene mutation analysis of 2 inherited PSD pedigrees with nonsense mutations.MethodsRetrospective analysis of clinical and imaging data of 2 patients diagnosed with CVST who were treated in the Department of Neurology,the First Affiliated Hospital of Wenzhou Medical University in July and October 2023 was carried out.The peripheral blood samples were collected from proband 1 and her family members(3 subjects,2 generations in total),and proband 2 and his family members(8 subjects of 3 generations in total).Their protein S(PS)activity(PS:A),the content of total PS antigen(TPS:Ag)and free PS antigen(FPS:Ag)were measured for definite diagnosis.Polymerase chain reaction was done in all 15 exons of the active PROS1 gene and its 5′and 3′untranslated regions and the amplification products were analyzed by direct sequencing.The results were compared with human PROS1 reference sequences,using Chromas software to find the mutation sites.ResultsThe proband 1 is a female,and the proband 2 is a male.Both of them had young onset and the clinical presentation of CVST.The PS:A level was reduced to 29%in the proband 1 and reduced to about 35%in her mother;PS:A was reduced to 21%-27%in the proband 2 and his 6 family members;a decline in the same proportion of TPS:Ag and FPS:Ag was found in the 2 probands and their family members,therefore they were primarily diagnosed as typeⅠPSD.Gene analysis showed that the proband 1 and her mother had a nonsense mutation of c.1680T>A in exon 14(p.Tyr560*)of the PROS1 gene;the proband 2 and his 6 family members had a nonsense mutation of c.1687C>T in exon 14(p.Gln563*)of the PROS1 gene.ConclusionThe reduced protein S levels in PSD patients and their family members may be associated with the p.Tyr560*and p.Gln563*nonsense mutations of the PROS1 gene,and the clinical manifestations of CVST in PSD patients may be related to these 2 nonsense mutations.

关 键 词：蛋白S缺陷 遗传 无义突变 血栓形成 终止密码子 

分 类 号：R743[医药卫生—神经病学与精神病学]