No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

AimsLikely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.MethodsWe screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] PLEC variant.ResultsForty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.ConclusionsAlthough PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.目的：编码桥粒蛋白（desmosomal proteins）的基因中，疑似致病/致病变异在致心律失常性右心室心肌病（arrhythmogenic right ventricular cardiomyopathy, ARVC）的病理生理过程中发挥关键作用。然而，仍有相当比例的ARVC患者尚未明确其遗传致病基础。我们提出假说：由PLEC基因编码的细胞连接蛋白网蛋白（plectin）可能参与ARVC的发病机制，因为已有研究证实其可将桥粒蛋白桥粒斑蛋白（desmoplakin）连接至细胞骨架，因此在桥粒结构的维持中具备潜在功能。 方法：我们对359例ARVC患者的PLEC基因进行筛查，并对比罕见编码区PLEC变异的发生频率（次要等位基因频率[MAF]）与对照组的差异。 结果：40例ARVC患者携带1种或多种罕见PLEC变异（占比11%，40/359）。然而，对照组人群中罕见变异的检出频率同样较高（18%，4754/26197例个体）。我们亦未发现，携带或不携带桥粒疑似致病/致病变异的ARVC患者之间，罕见PLEC变异的检出率存在差异（分别为14%与8%）。不过，免疫荧光分析（immunofluorescence analysis）确实显示，5例携带PLEC变异的ARVC患者的心肌组织中，网蛋白的连接定位出现显著减弱。 结论：尽管此前曾将PLEC假说为ARVC的潜在候选基因，但本研究并未发现ARVC患者的罕见PLEC变异富集程度高于对照组，因此不支持PLEC在该疾病中发挥主要致病作用。尽管罕见PLEC变异与心脏组织中网蛋白的异常定位相关，但综合现有数据并不支持网蛋白异常参与ARVC的发生发展。