DSG2基因p.Phe531Cys纯合突变所致致心律失常性右心室心肌病家系的临床表型和遗传学分析  

Clinical phenotype and genetic analysis of a family with arrhythmogenic right ventricular cardiomyopathy due to a homozygous mutation in DSG2(p.Phe531Cys)

作　　者：徐文静 程维礼 方旭 张莱 张郁青 陶琴 Xu Wenjing;Cheng Weili;Fang Xu;Zhang Lai;Zhang Yuqing;Tao Qin(Department of Cardiology,the Affiliated Jiangning Hospital of Nanjing Medical University,Nanjing 211100,China;State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]南京医科大学附属江宁医院心血管内科,211100 [2]中国药科大学多靶标天然药物全国重点实验室,南京211198

出　　处：《中国心血管杂志》2024年第4期332-337,共6页Chinese Journal of Cardiovascular Medicine

基　　金：南京市卫生科技发展专项资金项目(YKK20195);中国药科大学多靶标天然药物全国重点实验室开放研究基金(SKLNMKF202307)。

摘　　要：目的对桥粒芯糖蛋白2(DSG2)基因p.Phe531Cys罕见纯合突变所致致心律失常性右心室心肌病(ARVC)一个家系的基因型-表型进行分析,并对突变位点进行生物信息学分析。方法临床观察性研究。收集2022年7月于南京医科大学附属江宁医院心血管内科住院的1例确诊为ARVC的先证者及其家系成员的临床资料进行评估。采集静脉血进行二代测序,并用Sanger测序验证。从美国国家生物技术信息中心(NCBI)数据库获取DSG2基因野生型氨基酸序列,通过人工编辑获得突变型氨基酸序列,对DSG2蛋白二级及三级结构进行预测分析。结果先证者(Ⅲ2)符合ARVC诊断标准,其余家系成员均不符合。先证者为DSG2基因p.Phe531Cys纯合突变,先证者女儿(Ⅳ1)携带DSG2基因杂合突变。生物信息学分析提示,该突变位点在脊椎动物中保守性较好,氨基酸突变后蛋白质稳定性降低。突变型DSG2及野生型DSG2蛋白质二级结构无明显差异,三级结构突变位点处的折叠角度发生变化。结论DSG2基因p.Phe531Cys纯合突变可导致ARVC,不同的基因型可导致不同的临床表现。Objective To investigate the genotype-phenotype correlations and bioinformatics analysis of arrhythmogenic right ventricular cardiomyopathy(ARVC)caused by homozygous mutation of DSG2 p.Phe531Cys in a Chinese family.Methods This was a clinical observational study.The clinical data of proband with ARVC and his family members were collected and evaluated,the proband was admitted to Department of Cardiology,the Affiliated Jiangning Hospital of Nanjing Medical University in July 2022.Venous blood was collected for second generation sequencing,and verified by Sanger sequencing.The wild type amino acid sequences of DSG2 gene were obtained from National Center for Biotechnology Information(NCBI)database,and the mutant amino acid sequences were obtained by manual editing.And secondary and tertiary structures of the proteins were predicted by a computer.Results The proband met the diagnostic criteria of ARVC,but the rest of the relatives did not.The proband was identified as having a DSG2gene p.Phe531Cys homozygous mutation,his daughter carried a heterozygous mutation in the DSG2 gene.The bioinformatics analysis showed that the mutant site was well conserved in vertebrates,and the amino acid change caused by the mutation reduced the protein stability.The secondary structure prediction showed that there was no significant difference between the mutant DSG2 and the wild type DSG2.The results of tertiary structure prediction showed that the angle at the corner of the mutated DSG2 protein changed.Conclusions A homozygous mutation of DSG2 p.Phe531Cys is consider as the pathogenic mutation in patients with ARVC.Different genotypes can lead to varied clinical manifestations.

关 键 词：致心律失常性右心室心肌病 桥粒芯糖蛋白2基因 纯合突变 蛋白质结构 

分 类 号：R541.7[医药卫生—心血管疾病] R542.2[医药卫生—内科学]