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

  • Sunil Yadav
  • Yoel H. Sitbon
  • Katarzyna Kazmierczak
  • Danuta Szczesna-CordaryEmail author
Invited Review


Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are among 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, and 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 levels. 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.


Cardiomyopathy mutations Myosin regulatory light chain Myosin essential light chain Human phenotype Transgenic mice 


Funding information

This work was supported by the National Institutes of Health R01-HL123255 (DSC) and the American Heart Association 17PRE33650085 (SY).


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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Molecular and Cellular PharmacologyUniversity of Miami Miller School of MedicineMiamiUSA

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