Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach

Abstract

The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non-sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM.

De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents

“…Pediatric cardiomyopathies (CM) are very rare heterogeneous disorders of the cardiac muscle, but they are usually characterized by a rapid disease progression with a poor prognosis and high mortality [1,2]. The most common CMs in children <18 years are dilated (DCM) and hypertrophic CM (HCM), whereas non-compaction (NCM) and restrictive CM (RCM) are the most uncommon ones.…”

“…In pediatric CMs, de novo mutations seem to be more frequent and are linked to an especially severe disease development. Specific pharmacological treatments are still missing, especially for familial RCM and NCM; hence, heart transplantation is needed for survival [2]. Furthermore, the molecular mechanisms underlying the pathogenesis of RCM and NCM are not yet fully understood due to insufficient genetic testing and too few mechanistic studies.…”

“…In contrast, RCM is considered as a functional disease characterized by diastolic dysfunction, impaired relaxation, and increased myocardial stiffness. Both CMs are connected to malignant arrhythmia [2]. Furthermore, nearly all CMs are characterized by a disturbed protein quality control system, leading to increased protein aggregation, apoptosis, and fibrosis [8][9][10].…”

“…Structural and functional characterization of some RCM cases indicated the existence of mutation-induced myofilament dysfunctions, such as alterations of Ca 2+ -sensitivity, acto-myosin ATPase activity, and force generation. All these processes are prominently regulated by the heterotrimeric cardiac troponin complex (cTn), whose genes are frequently targets for RCM and NCM mutations, though no studies on the molecular level are available in case of NCM [2,11,12]. cTn is associated with the thin filament and consists of three subunits (Figure 1).…”

“…Most pediatric RCM mutations are point mutations, leading to single amino acid replacements in this region of cTnI. In TNNC1 encoding cTnC, only a few pathogenic modifications have been identified, mostly correlated to DCM or HCM [2], but at least 5 mutations have been described which induce non-compaction cardiomyopathy [12].…”