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ResearchIn-Press PreviewCardiology Open Access | 10.1172/JCI179135
1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
Find articles by Rynkiewicz, M. in: JCI | PubMed | Google Scholar
1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
Find articles by Moore, J. in: JCI | PubMed | Google Scholar
1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
Find articles by Lehman, W. in: JCI | PubMed | Google Scholar
1Department of Biomedical Engineering, Yale University, New Haven, United States of America
2Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, United States of America
3Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, United States of America
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Published October 22, 2024 - More info
Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the ‘closed’ regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.