Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies

Abstract

Purpose of review: The pace of identifying cardiomyopathy-associated mutations and advances in our understanding of sarcomere function that underlies many cardiomyopathies has been remarkable. Here, we aim to synthesize how these advances have led to the promising new treatments that are being developed to treat cardiomyopathies.

Recent findings: The genomics era has identified and validated many genetic causes of hypertrophic and dilated cardiomyopathies. Recent advances in our mechanistic understanding of sarcomere pathophysiology include high-resolution molecular models of sarcomere components and the identification of the myosin super-relaxed state. The advances in our understanding of sarcomere function have yielded several therapeutic agents that are now in development and clinical use to correct contractile dysfunction-mediated cardiomyopathy. New genes linked to cardiomyopathy include targets with limited clinical evidence and require additional investigation. Large portions of cardiomyopathy with family history remain genetically undiagnosed and may be due to polygenic disease.

Keywords: Cardiomyopathy; DCM; HCM; Myofilament; Sarcomere.

Fig. 1.

Schematic of the sarcomere proteins linked with cardiomyopathy. A, Half-sarcomere from Z-disk to M-line with isotropic (I) and anisotropic (A) bands labeled. The C-zone is defined as the ~350 nm wide portion of the myosin thick filament where cMyBP-C is localized in ventricular sarcomeres. The H-zone is the region with no actin overlap and no myosin heads. B, Schematic with gene and protein names of the cardiac thin filament with general mechanism of cardiomyopathies listed. C, Schematic of the cardiac thick filament. Phosphorylatable regulatory regions are marked with six-point stars, with yellow stars indicating phopshorylation. Mechanisms of cardiomyopathy causing mutations listed below the gene names.