ArticleAmerican journal of physiology. Heart and circulatory physiology2014
Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy.
Article in American journal of physiology. Heart and circulatory physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 52 citations in OpenAlex.
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- MYBPC3 (c.194 C > T) mutation-mediated RyR2 dysfunction contributes to pathogenic phenotypes of DCM revealed by HiPSC modeling.Cellular and molecular life sciences : CMLS · 2026Article
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Single Cell Transcriptomic Profiling ofJournal of the American Heart Association · 2025Article
- Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation.American journal of physiology. Heart and circulatory physiology · 2024Article
- Fine tuning contractility: atrial sarcomere function in health and disease.American journal of physiology. Heart and circulatory physiology · 2024Review
- Hypertrophic cardiomyopathy inThe journal of cardiovascular aging · 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
- Western diet triggers cardiac dysfunction in heterozygousJournal of molecular and cellular cardiology plus · 2023Article
- A pathogenic nonsense mutation (c.1522C>T) of the MYBPC3 gene is implicated with hypertrophic cardiomyopathy.ESC heart failure · 2023Article
- Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?The Journal of general physiology · 2023Article
- cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities.The Journal of general physiology · 2023Article
- Dynamic mechanobiology of cardiac cells and tissues: Current status and future perspective.Biophysics reviews · 2023Review
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- Preventative therapeutic approaches for hypertrophic cardiomyopathy.The Journal of physiology · 2021Review
- South Asian-SpecificFrontiers in cardiovascular medicine · 2021Article
- Phosphorylation of cardiac myosin-binding protein-C contributes to calcium homeostasis.The Journal of biological chemistry · 2020Article
- Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3Biophysical reviews · 2020Review
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4 authors at 1 institution in 1 country.
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Abstract
The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C'-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm(2) vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm(2) vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E'/A' (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.
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