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3. MYOCARDIAL IMPACT OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) SECRETOMES IN CARDIO-ONCOLOGY PATIENTS

Author

Kwan, Jennifer, primary, Vanoudenhove, Jennifer, additional, Halder, Saiti, additional, Biancon, Giulia, additional, Jain, Kanika, additional, Chakraborty, Raja, additional, Lustberg, Maryam, additional, Pusztai, Lajos, additional, Campbell, Stuart, additional, Zhao, Hongyu, additional, Halene, Stephanie, additional, and Hwa, John, additional

Published
2022
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8. Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants.

Author

Halder SS, Rynkiewicz MJ, Kim L, Barry M, Zied AG, Sewanan LR, Kirk JA, Moore JR, Lehman W, and Campbell SG

Abstract

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.

Published
2024
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