ArticleJournal of molecular and cellular cardiology2015
Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice.
Article in Journal of molecular and cellular cardiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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56 citing papers in PubMed, 74 citations in OpenAlex.
- Biomechanical stress unmasks a fibroblast-dependent hypercontractile-disarray phenotype in MYBPC3 truncation HCM.APL bioengineering · 2026Article
- Gene therapy in cardiac and vascular diseases: a review of approaches to treat genetic and common cardiovascular diseases with novel gene-based therapeutics.Cardiovascular research · 2025Review
- Missense variants in the myosin binding domains ofbioRxiv : the preprint server for biology · 2025Article
- Spatially resolving how cMyBP-C phosphorylation and haploinsufficiency in porcine and human myofibrils affect β-cardiac myosin activity.The Journal of general physiology · 2025Article
- Hypertrophic Cardiomyopathy-Associated CRYABInternational journal of molecular sciences · 2025Article
- Myocardial dysfunction caused by MyBPC3 P459fs mutation in hypertrophic cardiomyopathy: evidence from multi-omics approaches and super-resolution imaging.Frontiers in cardiovascular medicine · 2025Article
- Article
- Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation.American journal of physiology. Heart and circulatory physiology · 2024Article
- Substrate mechanics unveil early structural and functional pathology in iPSC micro-tissue models of hypertrophic cardiomyopathy.iScience · 2024Article
- Dynamic control of contractile resistance to iPSC-derived micro-heart muscle arrays.Journal of biomedical materials research. Part A · 2024Article
- Myosin-binding protein H-like regulates myosin-binding protein distribution and function in atrial cardiomyocytes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Unlocking the Role of sMyBP-C: A Key Player in Skeletal Muscle Development and Growth.bioRxiv : the preprint server for biology · 2023Article
- An Unbiased Screen Identified the Hsp70-BAG3 Complex as a Regulator of Myosin-Binding Protein C3.JACC. Basic to translational science · 2023Article
- 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
- cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities.The Journal of general physiology · 2023Article
- Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?The Journal of general physiology · 2023Article
- Mousepost 2.0, a major expansion of the resource.Nucleic acids research · 2023Article
- A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction.Frontiers in cardiovascular medicine · 2023Article
- Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model.International journal of molecular sciences · 2022Article
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7 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in MYBPC3, the gene encoding cardiac myosin binding protein-C (cMyBP-C), account for ~40% of hypertrophic cardiomyopathy (HCM) cases. Most pathological MYBPC3 mutations encode truncated protein products not found in tissue. Reduced protein levels occur in symptomatic heterozygous human HCM carriers, suggesting haploinsufficiency as an underlying mechanism of disease. However, we do not know if reduced cMyBP-C content results from, or initiates the development of HCM. In previous studies, heterozygous (HET) mice with a MYBPC3 C'-terminal truncation mutation and normal cMyBP-C levels show altered contractile function prior to any overt hypertrophy. Therefore, this study aimed to test whether haploinsufficiency occurs, with decreased cMyBP-C content, following cardiac stress and whether the functional impairment in HET MYBPC3 hearts leads to worsened disease progression. To address these questions, transverse aortic constriction (TAC) was performed on three-month-old wild-type (WT) and HET MYBPC3-truncation mutant mice and then characterized at 4 and 12weeks post-surgery. HET-TAC mice showed increased hypertrophy and reduced ejection fraction compared to WT-TAC mice. At 4weeks post-surgery, HET myofilaments showed significantly reduced cMyBP-C content. Functionally, HET-TAC cardiomyocytes showed impaired force generation, higher Ca(2+) sensitivity, and blunted length-dependent increase in force generation. RNA sequencing revealed several differentially regulated genes between HET and WT groups, including regulators of remodeling and hypertrophic response. Collectively, these results demonstrate that haploinsufficiency occurs in HET MYBPC3 mutant carriers following stress, causing, in turn, reduced cMyBP-C content and exacerbating the development of dysfunction at myofilament and whole-heart levels.
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