家族性心房颤动家系携带NEXN和JPH2基因突变分析

Mutation Analysis of NEXN and JPH2 Genes in a Family with Familial Atrial Fibrillation

目的使用全外显子测序技术对收集的1例心房颤动患者家系进行致病基因筛查及突变位点分析,初步探索该基因的生物学机制。方法采集此家族成员外周静脉血,提取基因组DNA,应用全外显子测序技术对先证者进行候选基因突变检测,发现可疑致病位点后,通过Sanger测序法在其家系成员和101例健康人群中进行验证。并使用Polyphen2、MutationTaster和Provean三种软件进行突变基因功能检测,利用Swiss-Model软件分析致病基因突变前后的蛋白质三维结构模型。结果该家系除先证者外,4例携带NEXN c.919C>A(p.P307T)杂合变异,2例携带JPH2 c.1088G>A(p.R363H)杂合变异,先证者及其父亲同时携带以上两种突变基因,而101例健康人均未携带上述两种突变。两种突变所在区域的氨基酸序列高度保守,三种计算机预测软件预测这两种突变均为致病性突变。结论该家系多位成员携带NEXN c.919C>A(p.P307T)杂合突变和JPH2 c.1088G>A(p.R363H)杂合突变,这两种基因变异与该家系成员心房颤动的发生密切相关,该变异可能是该家系心房颤动的致病基因突变位点。

Objective To screen the pathogenic gene and analyze the mutation sites in a family of patients with atrial fibrillation by full exon sequencing,and to explore the biological mechanism of the gene.Methods Genomic DNA was extracted from the peripheral venous blood of the family members,and the candidate gene mutations were detected by full exon sequencing.After the suspicious pathogenic sites were found,Sanger sequencing method was used to verify the results in the family members and 101 healthy people.Polyphen2,MutationtTaster and Provean software were used to detect the function of the mutant gene,and Swiss-Model software was used to analyze the three-dimensional structure model of the protein before and after the mutation of the pathogenic gene.Results Except for the proband,4 cases carried the NEXN c.919C>A(p.P307T)heterozygous mutation and 2 cases carried the JPH2 c.1088G>A(p.R363H)heterozygous mutation.The proband and his father carried both the above two mutant gene,while 101 healthy people did not carry the above two mutations.The amino acid sequences of the two mutations were highly conserved,and the three computer prediction software predicted that the two mutations were pathogenic.Conclusion Many members of the family carry the NEXN c.919C>A(p.P307T)heterozygous mutation and JPH2 c.1088G>A(p.R363H)heterozygous mutation,which are closely related to the occurrence of atrial fibrillation in the family members,and may be the pathogenic gene mutation site of atrial fibrillation in the family.