ArticleThe Journal of biological chemistry2011
Molecular mechanism of the E99K mutation in cardiac actin (ACTC Gene) that causes apical hypertrophy in man and mouse.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 66 citations in OpenAlex.
- Multiple triggering mechanisms of myocardial fibrosis: Comparison and integration in different disease contexts.iScience · 2026Review
- Actomyosin-Based Nanodevices for Sensing and Actuation: Bridging Biology and Bioengineering.Biosensors · 2025Review
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- A Cautionary Tale of Hypertrophic Cardiomyopathy-From "Benign" Left Ventricular Hypertrophy to Stroke, Atrial Fibrillation, and Molecular Genetic Diagnostics: A Case Report and Review of Literature.International journal of molecular sciences · 2024Review
- Article
- Myofilament dysfunction in diastolic heart failure.Heart failure reviews · 2024Review
- Nutraceuticals silybin B, resveratrol, and epigallocatechin-3 gallate-bind to cardiac muscle troponin to restore the loss of lusitropy caused by cardiomyopathy mutationsFrontiers in physiology · 2024Article
- Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A.Journal of muscle research and cell motility · 2023Review
- Suppression of lusitropy as a disease mechanism in cardiomyopathies.Frontiers in cardiovascular medicine · 2022Review
- Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.Frontiers in cardiovascular medicine · 2022Review
- Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics.Journal of molecular and cellular cardiology · 2020Article
- Actin Mutations and Their Role in Disease.International journal of molecular sciences · 2020Review
- Pressure Overload Is Associated With Low Levels of Troponin I and Myosin Binding Protein C Phosphorylation in the Hearts of Patients With Aortic Stenosis.Frontiers in physiology · 2020Article
- MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.Cell stem cell · 2019Article
- Mutations inF1000Research · 2019Article
- Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.Stem cell reports · 2018Article
- Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle.International journal of molecular sciences · 2018Review
- The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy.International journal of molecular sciences · 2018Review
- Simplified Footprint-Free Cas9/CRISPR Editing of Cardiac-Associated Genes in Human Pluripotent Stem Cells.Stem cells and development · 2018Article
- Classifying Cardiac Actin Mutations Associated With Hypertrophic Cardiomyopathy.Frontiers in physiology · 2018Review
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
Abstract
We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to β-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.
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