Structural consequences of mutations associated with idiopathic restrictive cardiomyopathy

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.