云南不明原因猝死ARVC病理诊断病例家庭桥粒蛋白基因突变研究  

Desmosomal protein gene mutations of Yunnan unexplained sudden death cases families by ARVC pathological diagnosis

作　　者：王跃兵 马琳 唐雪 杨林 习严梅 孙梦遥 董毅 黄文丽 雷普平 Wang Yuebing;Ma Lin;Tang Xue;Yang Lin;Xi Yanmei;Sun Mengyao;Dong Yi;Huang Wenli;Lei Puping(Public Health Emergency Office,Yunnan Institute of Endemic Disease Control and Prevention,Dali 671000,China;Department of Forensic Medicine of Kunming Medical University,Kunming 650500,China)

机构地区：[1]海南省地方病防治所卫生应急办公室,大理671000 [2]昆明医科大学法医学院,650500

出　　处：《中华地方病学杂志》2020年第8期551-556,共6页Chinese Journal of Endemiology

基　　金：国家自然科学基金(81960573、81460285);云南公共卫生与疾病防控协同创新中心项目(2014YNPHXT13);徐建国院士工作站项目(2018IC155);陈义汉院士工作站建设基金(2019IC018);昆明医科大学创新团队(CXTD201803)。

摘　　要：目的探讨云南不明原因猝死(简称云南猝死)与致心律失常性右室心肌病(ARVC)桥粒蛋白基因突变之间的病因联系。方法以4个云南猝死ARVC病理诊断病例家庭为研究对象,收集家庭内的云南猝死ARVC病理诊断病例(n=3)尸解心腔血,采集与其有血缘遗传关系的直系亲属(病例亲属,n=4)和无血缘遗传关系的对照人群(n=7)静脉血,提取DNA进行ARVC桥粒蛋白基因桥粒斑菲素蛋白2(PKP2)、桥粒斑蛋白(DSP)、桥粒芯蛋白2(DSG2)、桥粒芯胶蛋白2(DSC2)、连接桥粒斑珠蛋白(JUP)共97个外显子位点的PCR扩增及测序,结合遗传家系综合分析5个基因的突变情况。结果云南猝死ARVC病理诊断病例及病例亲属全部发生DSP基因突变,PKP2、DSG2、DSC2和JUP基因突变各1人,同一人同时携带1~3个基因突变。DSP基因存在4个外显子突变位点,其中1个为新发现杂合同义突变c.4014 C>A(p.A1338A)。1例云南猝死ARVC病理诊断病例同时携带PKP2基因的2个错义突变位点,且1个为新发现杂合子突变c.739 G>C(p.G247R)。新发现JUP基因的1个杂合错义突变位点c.799 G>A(p.A267T),其蛋白质功能预测值高达0.963,蛋白质功能发生异常改变的可能性较高。DSG2和DSC2基因各有1个突变位点。对照人群均未发现上述突变。结论云南猝死ARVC病理诊断病例及病例亲属携带ARVC桥粒蛋白基因DSP、PKP2、DSG2、DSC2、JUP突变,推测部分云南猝死与ARVC桥粒蛋白基因突变间可能具有一定的病因关联。Objective To expound the pathogenesis relationship between Yunnan unexplained sudden death(YUSD)and desmosomal protein gene mutations of arrhythmogenic right ventricular cardiomyopathy(ARVC).Methods Four YUSD cases families by ARVC pathological diagnosis were selected,to collect heart blood samples of YUSD cases by ARVC pathological diagnosis(n=3),venous blood samples of immediate relatives with genetic relationship(case relatives,n=4)and control population without genetic relationship(n=7).DNA was extracted for PCR amplification and sequencing of a total of 97 exons of the ARVC desmosomal protein genes plakophilin 2(PKP2),desmoplakin(DSP),desmoglein 2(DSG2),desmocollin 2(DSC2),and junction plakoglobin(JUP),and the mutations of the 5 genes were analyzed in combination with the genetic family.Results DSP gene mutations were found in all YUSD cases by ARVC pathological diagnosis and case relatives,and PKP2,DSG2,DSC2 and JUP genes mutations were found in 1 person each.The same person carried 1-3 genes mutations.DSP gene existed 4 exon mutation sites,and 1 of which was a newly discovered heterozygous synonymous mutation c.4014 C>A(p.A1338A).PKP2 gene existed 2 exon missense mutation sites in 1 YUSD case by ARVC pathological diagnosis,and 1 of which was a newly discovered heterozygous mutation c.739 G>C(p.G247R).One heterozygous missense mutation site c.799 G>A(p.A267T)of JUP gene was newly discovered,and the predictive value of protein function was 0.963,the possibility of abnormal changes in protein function was high.DSG2 and DSC2 genes each had one mutation site.However,no mutation was found in control population.Conclusions Both YUSD cases by ARVC pathological diagnosis and case relatives carry ARVC desmosomal protein genes DSP,PKP2,DSG2,DSC2 and JUP mutations.There may be a certain pathogenesis relationship between YUSD and ARVC desmosomal protein gene mutations.

关 键 词：猝死 心脏 致心律失常性右室心肌病 桥粒蛋白基因 

分 类 号：R541.78[医药卫生—心血管疾病]