Department of Bioinformatics, Peter the Great Saint Petersburg Polytechnic University, St. Petersburg, 195251, Russian Federation.
Federal Almazov North-West Medical Research Centre, St. Petersburg, 197341, Russian Federation.
Amino Acids. 2017 Nov;49(11):1815-1829. doi: 10.1007/s00726-017-2480-8. Epub 2017 Aug 22.
Idiopathic restrictive cardiomyopathy (RCM, MIM# 115210) is the least common type of cardiomyopathies, often of genetic origin. Recently we described a spectrum of variants-classified as pathogenic, likely pathogenic and variants of unknown significance-in 24 patients suffering from idiopathic RCM. Pathogenic variants, detected in half of the RCM cases, were found in sarcomeric and cytoskeletal genes that have a predominant role in the development of RCM. Here we have analyzed the structural consequences of these missense variants and predicted their effect on the function of three large groups of domains: intrinsically disordered regions (IDRs), fibronectin-type III (FnIII) domains, and immunoglobulin-like (Ig) domains. Our findings indicate that pathogenic mutations are likely to disrupt interdomain interfaces, interfere with protein interactions, and affect protein stability, potentially destabilizing the multi-domain architecture of myofibrils and leading to myocardial stiffness in patients with idiopathic RCM.
特发性限制性心肌病（RCM，MIM#115210）是最不常见的心肌病类型，通常具有遗传起源。最近，我们在 24 名患有特发性 RCM 的患者中描述了一系列变体——归类为致病性、可能致病性和意义不明的变体。在一半的 RCM 病例中检测到的致病性变体存在于肌节和细胞骨架基因中，这些基因在 RCM 的发展中起主要作用。在这里，我们分析了这些错义变体的结构后果，并预测了它们对三大类结构域功能的影响：无规则卷曲区域（IDRs）、纤维连接蛋白 III 型（FnIII）结构域和免疫球蛋白样（Ig）结构域。我们的研究结果表明，致病性突变可能破坏结构域间界面，干扰蛋白相互作用，并影响蛋白稳定性，可能使肌原纤维的多结构域结构不稳定，导致特发性 RCM 患者心肌僵硬。
