Key result
TPM1 S215L variant induces hypercontractility and diastolic dysfunction, supporting its pathogenic role in HCM.
Why the study?
Many HCM-associated TPM1 variants vary in severity, and the pathogenicity of many detected in clinical populations remains unknown.
Does the TPM1 S215L variant cause hypertrophic cardiomyopathy phenotypes in computational and engineered heart tissue models?
Does the TPM1 S215L variant cause hypertrophic cardiomyopathy phenotypes in computational and engineered heart tissue models?
The TPM1 S215L variant is pathogenic for hypertrophic cardiomyopathy, driven by an inability to adequately inhibit actomyosin interactions leading to hypercontractility and diastolic dysfunction.
Supports TPM1 S215L reclassification in HCM; leaves open human translation from animal models.
Hypertrophic cardiomyopathy (HCM) is an inherited disorder often caused by mutations to sarcomeric genes. Many different HCM-associated TPM1 mutations have been identified but they vary in their degrees of severity, prevalence, and rate of disease progression. The pathogenicity of many TPM1 variants detected in the clinical population remains unknown. Our objective was to employ a computational modeling pipeline to assess pathogenicity of one such variant of unknown significance, TPM1 S215L, and validate predictions using experimental methods. Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain. These changes were quantitatively represented in a Markov model of thin-filament activation to infer the impacts of S215L on myofilament function. Simulations of in vitro motility and isometric twitch force predicted that the mutation would increase Ca2+ sensitivity and twitch force while slowing twitch relaxation. In vitro motility experiments with thin filaments containing TPM1 S215L revealed higher Ca2+ sensitivity compared with wild type. Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction. These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype. These simulations and experiments support the classification of S215L as a pathogenic mutation and support the hypothesis that an inability to adequately inhibit actomyosin interactions is the mechanism whereby thin-filament mutations cause HCM.
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Halder et al. (2023) studied Hypertrophic cardiomyopathy. TPM1 S215L variant vs. Wild type was evaluated on Pathogenicity and functional impact (Ca2+ sensitivity, hypercontractility, diastolic dysfunction). The TPM1 S215L variant increased Ca2+ sensitivity, induced hypercontractility, and caused diastolic dysfunction compared with wild type, supporting its classification as a pathogenic mutation in HCM.
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