Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy
Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy
复制标题
DOI：
10.1161/circulationaha.105.561654
复制
发表时间：
2006-01-24
期刊：
影响因子：
37.8
通讯作者：
McKenna, WJ
中科院分区：
文献类型：
--
作者：
Syrris, P;Ward, D;McKenna, WJ
背景-致心律失常性右心室心肌病（ARVC）是一种遗传性心脏疾病，其特征是心肌细胞丢失并被脂肪和纤维组织替代。它被认为是一种细胞粘附疾病，因为桥粒基因，桥粒斑蛋白和斑珠蛋白的突变与ARVC的发病机制有关。在最近的一份报告中，plakophilin-2，心脏桥粒中高度表达的基因突变，已被证明是导致ARVC.Methods和结果-我们调查了100例白色ARVC患者的plakophilin-2突变。在11例病例中通过直接测序鉴定出9种不同的突变。这些突变中有5个是新的（A733 fsX 740、L586 fsX 658、V570 fsX 576、R413 X和P533 fsX 561），并预测会导致斑嗜蛋白-2蛋白的过早截短。家庭研究表明，突变携带者的不完整的疾病表达，并确定了一些个人谁会被误诊与现有的国际工作组和修改后的诊断标准ARVC.Conclusions -在这项研究中，我们提供了新的证据，桥粒斑嗜蛋白-2基因的突变可以导致ARVC。对家族内突变携带者的系统性临床评价表明，即使在具有相同突变的个体中，表型表达也是可变的，并强调需要一套更准确的ARVC诊断标准。
Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.