ArticleThe Journal of biological chemistry2015
A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 29 citations in OpenAlex.
- An RYR2-interacting fragment of MYBPC3 mitigates arrhythmia in human iPSC-CM and mouse models of CPVT.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Myosin motor dynamics and cardiac function: Insights from in vivo small-angle X-ray scattering and pressure-volume analysis.The Journal of physiology · 2026Article
- Knowledge mapping of targeted therapy for hypertrophic cardiomyopathy: A bibliometric analysis of myosin inhibitor research.Medicine · 2026Article
- Hypertrophic cardiomyopathy: comprehensive insights into pathogenic genes and genotype-phenotype associations.Frontiers in cell and developmental biology · 2026Review
- Myosin-binding protein C slows cardiac myofibril relaxation kinetics.The Journal of physiology · 2025Article
- An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2023Review
- Mechanisms of Sarcomere Protein Mutation-Induced Cardiomyopathies.Current cardiology reports · 2023Review
- Etiology of genetic muscle disorders induced by mutations in fast and slow skeletal MyBP-C paralogs.Experimental & molecular medicine · 2023Review
- Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double MutationInternational journal of molecular sciences · 2021Article
- South Asian-SpecificFrontiers in cardiovascular medicine · 2021Article
- Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3Biophysical reviews · 2020Review
- Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.Cardiovascular research · 2019Article
- Association of cardiac myosin-binding protein-C with the ryanodine receptor channel - putative retrograde regulation?Journal of cell science · 2018Article
- The HCM-linked W792R mutation in cardiac myosin-binding protein C reduces C6 FnIII domain stability.American journal of physiology. Heart and circulatory physiology · 2018Article
- Skeletal myosin binding protein-C isoforms regulate thin filament activity in a CaScientific reports · 2018Article
- Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy.Circulation · 2017Article
- Posttranslational modifications of calcium/calmodulin-dependent protein kinase IIδ and its downstream signaling in human failing hearts.American journal of translational research · 2017Article
- Comparative functional properties of engineered cationic antimicrobial peptides consisting exclusively of tryptophan and either lysine or arginine.Journal of medical microbiology · 2016Article
- Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes.Journal of cardiovascular translational research · 2016Article
- Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants.Frontiers in physiology · 2016Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-C(C10mut)), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-C(C10mut) in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca(2+) transients, compared with wild-type cMyBP-C expression (cMyBP-C(WT)) and controls. Forty-eight hours after infection, 44% of cMyBP-C(WT) and 36% of cMyBP-C(C10mut) protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-C(C10mut) to the C-zone, whereas cMyBP-C(WT) mostly showed C-zone staining, suggesting that cMyBP-C(C10mut) could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-C(C10mut) resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-C(C10mut) displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca(2+) transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10(mut) causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-C(C10mut), providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-C(C10mut) protein is sufficient to cause contractile dysfunction in vitro.
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