Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.

Autor:	Halder SS; Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA., Rynkiewicz MJ; Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA., Kim L; Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA., Barry ME; Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, USA., Zied AG; Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, Illinois, USA., Sewanan LR; Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA., Kirk JA; Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, Illinois, USA., Moore JR; Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, USA., Lehman WJ; Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA., Campbell SG; Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Dec 16; Vol. 134 (24). Date of Electronic Publication: 2024 Dec 16.
DOI:	10.1172/JCI179135
Abstrakt:	Heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) represent starkly diverging clinical phenotypes, yet may be caused by mutations to the same sarcomeric protein. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective was 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.
Databáze:	MEDLINE
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