Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 19; p. e2318413121
• Main Authors: Lee, Soah, Vander Roest, Alison S, Blair, Cheavar A, Kao, Kerry, Bremner, Samantha B, Childers, Matthew C, Pathak, Divya, Heinrich, Paul, Lee, Daniel, Chirikian, Orlando, Mohran, Saffie E, Roberts, Brock, Smith, Jacqueline E, Jahng, James W, Paik, David T, Wu, Joseph C, Gunawardane, Ruwanthi N, Ruppel, Kathleen M, Mack, David L, Pruitt, Beth L, Regnier, Michael, Wu, Sean M, Spudich, James A, Bernstein, Daniel
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.05.2024
• Subjects: Biological Sciences; Biomechanics; Cardiac Myosins - genetics; Cardiac Myosins - metabolism; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiovascular diseases; Cell Respiration - genetics; Cytoplasmic organelles; Gene regulation; Genetic modification; Genotypes; Humans; Hypertrophy; Induced Pluripotent Stem Cells - metabolism; Metabolism; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Muscle contraction; Mutation; Myocardial Contraction - genetics; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myofibrils; Myofibrils - metabolism; Myosin; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Pathogenicity; Pathogens; Phenotypes; Pluripotency; Proteins; Respiration; Stem cells; Structure-function relationships; Tissue; Transcriptomics; Transducers; hypertrophic cardiomyopathy; induced pluripotent stem cells; biomechanics; MYH7
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2318413121

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain ( ) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.