ArticleThe Journal of biological chemistry2012
A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 56 citations in OpenAlex.
- Hypertrophic cardiomyopathy-linked Tnnc1 variants are associated with distinct myopathic changes in slow skeletal muscle of mice.Journal of muscle research and cell motility · 2026Article
- Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.Circulation. Genomic and precision medicine · 2025Article
- Investigating the dual role of mitochondrial and nuclear genome variants in pediatric cardiomyopathies.Scientific reports · 2025Article
- Focus on cardiac troponin complex: From gene expression to cardiomyopathy.Genes & diseases · 2024Review
- Dilated Cardiomyopathy: A Genetic Journey from Past to Future.International journal of molecular sciences · 2024Review
- Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation.International journal of molecular sciences · 2023Review
- Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C.International journal of molecular sciences · 2023Review
- Calcium Handling in Inherited Cardiac Diseases: A Focus on Catecholaminergic Polymorphic Ventricular Tachycardia and Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2023Review
- The effect of MgThe FEBS journal · 2022Article
- Tissue-specific multi-omics analysis of atrial fibrillation.Nature communications · 2022Article
- Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.Frontiers in cardiovascular medicine · 2022Review
- Ion Channel Impairment and Myofilament CaCells · 2021Review
- Cardiomyocyte Dysfunction in Inherited Cardiomyopathies.International journal of molecular sciences · 2021Review
- De Novo Missense Mutations inInternational journal of molecular sciences · 2021Article
- Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach.Life (Basel, Switzerland) · 2021Article
- A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C.Journal of muscle research and cell motility · 2021Article
- Insights From Computational Modeling Into the Contribution of Mechano-Calcium Feedback on the Cardiac End-Systolic Force-Length Relationship.Frontiers in physiology · 2020Article
- The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation.The Journal of biological chemistry · 2019Article
- Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies.Journal of clinical medicine · 2019Review
- 'Heart development and morphogenesis' is a novel pathway for human ovarian granulosa cell differentiation during long‑term in vitro cultivation‑a microarray approach.Molecular medicine reports · 2019Article
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6 authors at 3 institutions in 1 country.
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Abstract
Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM. Here, we report clinical and functional characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death. Diagnosed at age 5, the proband is family history-negative for HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which increased Ca(2+) sensitivity with no effect on the maximal contractile force generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% cTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100% cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The secondary structure of the cTnC mutant was evaluated by circular dichroism, which did not indicate global changes in structure. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. These results suggest that this mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. In summary, we report a novel mutation in the TNNC1 gene that is associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM.
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