ArticleThe FEBS journal2015
Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain.
Article in The FEBS journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 44 citations in OpenAlex.
- Force-Induced Ankle Opening Reveals Mechanical Stabilization of the Ankle of Human β-Cardiac Myosin.ACS nano · 2026Article
- Modulating the myosin super-relaxed state as a therapeutic strategy for myosin light chain-linked cardiomyopathies.Biophysical reviews · 2026Review
- Bioinformatics-based screening of genes associated with dilated cardiomyopathy.Journal of thoracic disease · 2025Article
- Gender-Specific DNA Methylation Profiles Associated with Adult Weight in Hezuo Pigs.International journal of molecular sciences · 2024Article
- Dilated Cardiomyopathy: A Genetic Journey from Past to Future.International journal of molecular sciences · 2024Review
- Article
- In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused byFrontiers in physiology · 2024Article
- Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.Life (Basel, Switzerland) · 2023Article
- Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies.Current cardiology reports · 2023Review
- Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.International journal of molecular sciences · 2022Article
- Molecular basis of force-pCa relation inProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Understanding the molecular basis of cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2022Review
- Functional enrichment of alternative splicing events with NEASE reveals insights into tissue identity and diseases.Genome biology · 2021Article
- From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin.International journal of molecular sciences · 2021Review
- Retrospective Study of Intercalated Disk Defects Associated with Dilated Cardiomyopathy, Atrial Thrombosis, and Heart Failure in BALB/c Mice Deficient in IL4 Receptor α.Comparative medicine · 2020Article
- Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.PLoS genetics · 2020Article
- MYL6B drives the capabilities of proliferation, invasion, and migration in rectal adenocarcinoma through the EMT process.Open life sciences · 2020Article
- Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies.International journal of molecular sciences · 2019Review
- Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.Pflugers Archiv : European journal of physiology · 2019Review
- Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy.ESC heart failure · 2019Article
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Authors and funding
10 authors at 3 institutions in 1 country.
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Abstract
Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain (RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first-degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild-type (WT) and D94A mutant proteins, and performed in vitro experiments using RLC-mutant or WT-reconstituted porcine cardiac preparations. The mutation induced a reduction in the α-helical content of the RLC, and imposed intra-molecular rearrangements. The phosphorylation of RLC by Ca²⁺/calmodulin-activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild-type. No changes in the myofibrillar ATPase-pCa relationship were observed in wild-type- or D94A-reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross-section of muscle, with no change in the calcium sensitivity of force in D94A-reconstituted skinned porcine papillary muscle strips compared with wild-type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype.
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