Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

Abstract

Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are amongst the leading causes of morbidity and mortality worldwide. Such genetically-driven forms of hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability combined with genetic and phenotypic overlap between different cardiomyopathies, have challenged proper clinical prognosis and provided an incentive for identification of pathogenic variants. This review attempts to provide an overview of inherited cardiomyopathies with a focus on their genetic etiology in myosin regulatory (RLC) and essential (ELC) light chains, which are EF-hand protein family members with important structural and regulatory roles. From the clinical discovery of cardiomyopathy-linked light chain mutations in patients to an array of exploratory studies in animals, reconstituted, and recombinant systems, we have summarized the current state of knowledge on light chain mutations and how they induce physiological disease states via biochemical and biomechanical alterations at the molecular, tissue and organ level. Cardiac myosin RLC phosphorylation and the N-terminus ELC have been discussed as two important emerging modalities with important implications in the regulation of myosin motor function and thus cardiac performance. A comprehensive understanding of such triggers is absolutely necessary for the development of target-specific rescue strategies to ameliorate or reverse the effects of myosin light chain-related inherited cardiomyopathies.

Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3

“…Variants in MYL3 are rarely involved in familial cardiomyopathy, [4][5][6][7] and recessive LOF MYL3 variants, thus far, have not been described. The majority of reported variants are, however, associated with SCD at a young age.…”

“…Autosomal dominant and recessive variants in MYL3, which encodes the ventricular myosin essential light chain (ELC), are a rare cause of HCM with inter-and intrafamilial variability ranging from benign to malignant forms with cardiac failure and SCD. [3][4][5][6][7] It has also been suggested that MYL3 variants can result in variable morphological phenotypes. [7][8][9] There are, however, no reports of DCM associated with MYL3 variants or cardiomyopathy associated with likely ELC deficiency due to nonsense or essential splice acceptor variants in MYL3.…”

Mylk3null C57BL/6N mice develop cardiomyopathy, whereasNntnull C57BL/6J mice do not

“…We go on to show that the CM in B6N may be due to a null mutation in myosin light chain kinase 3 (Mylk3), which is only present in B6N substrains. MYLK3 phosphorylates myosin light chain 2 (MYL2), which is itself essential for the assembly of actin fibres in the heart and mutated in many human cases of CM (19,20).…”

Poor Myocardial Compaction in a Patient with Recessive <i>MYL2</i> Myopathy

“…Cardiac morphological phenotypes of recessive MYL2 myopathy have shown no clear correlation with the genotype. 1,5) Reported patients from two Italian families and 8 Dutch families, all harboring mutations affecting the last exon, have invariably experienced premature death, although cardiac morphology ranged from hypertrophic, dilated to noncompaction cardiomyopathy. 1) Another sibling, homozygous of the P144Rfs*57 variant, showed the hypertrophic phenotype, well contrasting with the noncompaction morphology of the presented case.…”