Dokuparti Maithili V N, Pamuru Pranathi Rao, Thakkar Bhavesh, Tanjore Reena R, Nallari Pratibha
Department of Genetics, University College of Science, Osmania University, Jamia Osmania Post Office, Hyderabad, 500 007, Andhra Pradesh, India.
King Edward Memorial Hospital, Parel, Mumbai, India.
J Hum Genet. 2005;50(8):375-381. doi: 10.1007/s10038-005-0273-5. Epub 2005 Aug 12.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibro-fatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca(2+) concentration by releasing Ca(2+) reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca(2+) levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFbeta-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca(2+) receptors.
致心律失常性右室心肌病（ARVC）的特征是右心室心肌进行性纤维脂肪替代。早期研究将ARVC描述为一种非炎性、非冠状动脉性疾病，与心律失常、心力衰竭以及由于右心室功能丧失导致的猝死有关。分子遗传学研究已确定9个与ARVC相关的不同基因座；因此，每个基因座与每种类型的ARVC（ARVC1 - ARVC9）相关。到目前为止，已确定5个基因含有ARVC的致病突变。尽管每个基因中的突变表明导致该疾病的不同途径受到破坏，但该疾病的确切发病机制仍不清楚。本综述试图通过研究相关的单个蛋白质来了解该疾病的发病机制，并将它们与可能在该疾病病因中起作用的途径联系起来。心脏兰尼碱受体（RYR - 2）是第一个被发现与ARVC相关的基因，它通过从肌浆网（SR）释放钙储备来调节细胞内钙（Ca2+）浓度。该基因的突变被认为会破坏RYR - 2的耦联门控，导致后去极化，进而引发心律失常，随后由于细胞内钙（Ca2+）水平改变导致结构变化。另外三个与ARVC相关的基因，即桥粒斑珠蛋白（纳克索斯病）、桥粒芯蛋白（ARVC8）和桥粒斑菲素蛋白（ARVC9），引发了关于ARVC主要是一种桥粒疾病的推测。但ARVC1中转化生长因子β - 3（TGFbeta - 3）的发现以及这三个基因（桥粒斑珠蛋白、桥粒芯蛋白和桥粒斑菲素蛋白）在心脏形态发生中的作用表明该疾病存在某种信号转导途径的破坏。ARVC作为乌尔畸形较轻形式的发现表明该疾病具有相似的个体发生过程。此外，在ARVC患者右心室心肌尸检中发现凋亡细胞确实表明不同类型的ARVC存在共同途径，该途径对涉及桥粒斑块蛋白、生长因子和钙（Ca2+）受体的右心室心肌更为特异。
