Whole-Exome Sequencing Identified a De Novo Mutation of Junction Plakoglobin (p.R577C) in a Chinese Patient with Arrhythmogenic Right Ventricular Cardiomyopathy
Whole-Exome Sequencing Identified a De Novo Mutation of Junction Plakoglobin (p.R577C) in a Chinese Patient with Arrhythmogenic Right Ventricular Cardiomyopathy
复制标题
全外显子组测序发现中国致心律失常性右心室心肌病患者存在连接斑珠蛋白 (p.R577C) 的从头突变
DOI：
10.1155/2019/9103860
复制
发表时间：
2019-01-01
影响因子：
--
通讯作者：
Yu, Rong
中科院分区：
文献类型：
--
作者：
Liu, Lv;Chen, Chan;Yu, Rong
致心律失常性右心室心肌病（ARVC）是一种罕见的和潜在的危及生命的心脏疾病。ARVC的临床谱包括肌细胞损失和纤维脂肪组织替代。随着ARVC的进展，患者可出现严重的室性心律失常、心力衰竭，甚至心源性猝死。以往的研究表明，桥粒和中间连接在ARVC的发生和发展中起着至关重要的作用。在这项研究中，我们招募了一名中国可疑ARVC患者。患者右心室增大，右心室壁增厚较少。心电图记录显示为A波。但是，他的父母没有明显的症状。在全外显子组测序和数据过滤后，我们在该患者中鉴定了连接斑珠蛋白（JUP）的从头突变（c.1729C>T/p.R577C）。生物信息学程序预测这种突变是有害的。Western blot结果显示，与野生型质粒转染的细胞相比，突变型质粒转染的细胞桥粒芯糖蛋白2（DSG 2）和连接蛋白43（Connexin 43）的表达明显降低。以往的研究表明，DSG 2和Connexin 43的减少可能会干扰桥粒的稳定性。在本研究中，我们报告了一个新的从头突变（c.1729C>T/p.R577C）的JUP在中国可疑的ARVC患者。功能研究进一步证实了这种新突变的致病性。我们的研究扩大了JUP突变的范围，可能有助于ARVC患者的遗传诊断和咨询。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare and potentially life-threatening disorder of the heart. The clinical spectrum of ARVC includes myocyte loss and fibro-fatty tissue replacement. With the progress of ARVC, the patient can present serious ventricular arrhythmias, heart failure, and even sudden cardiac death. Previous studies have demonstrated that desmosomes and intermediate junctions play a crucial role in the generation and development of ARVC. In this study, we enrolled a Chinese patient with suspicious ARVC. The patient suffered from right ventricular enlargement and less thickening of right ventricular wall. ECG record showed an epsilon wave. However, there was no obvious symptom in his parents. After whole-exome sequencing and data filtering, we identified a de novo mutation (c.1729C>T/p.R577C) of junction plakoglobin (JUP) in this patient. Bioinformatics programs predicted that this mutation was deleterious. Western blot revealed that, compared to cells transfected with WT plasmids, the expressions of desmoglein 2 (DSG2) and Connexin 43 were decreased overtly in cells transfected with the mutant plasmid. Previous studies have proven that the reduction of DSG2 and Connexin 43 may disturb the stability of desmosomes. In this research, we reported a novel de novo mutation (c.1729C>T/p.R577C) of JUP in a Chinese patient with suspicious ARVC. Functional research further confirmed the pathogenicity of this novel mutation. Our study expanded the spectrum of JUP mutations and may contribute to the genetic diagnosis and counseling of patients with ARVC.