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

Autor:	Lee S; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Department of Biopharmaceutical Convergence, Sungkyunkwan University School of Pharmacy, Suwon, Gyeonggi-do 16419 South Korea.; School of Pharmacy, Sungkyunkwan University School of Pharmacy, Suwon, Gyeonggi-do 16419, South Korea., Vander Roest AS; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109., Blair CA; Biological Engineering, University of California, Santa Barbara, CA 93106.; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536., Kao K; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Bremner SB; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Childers MC; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Pathak D; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305., Heinrich P; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Lee D; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Chirikian O; Biological Engineering, University of California, Santa Barbara, CA 93106., Mohran SE; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Roberts B; Allen Institute for Cell Science, Seattle, WA 98109., Smith JE; Allen Institute for Cell Science, Seattle, WA 98109., Jahng JW; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Paik DT; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305., Wu JC; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305., Gunawardane RN; Allen Institute for Cell Science, Seattle, WA 98109., Ruppel KM; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305., Mack DL; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Pruitt BL; Biological Engineering, University of California, Santa Barbara, CA 93106., Regnier M; Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195., Wu SM; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305., Spudich JA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305., Bernstein D; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.; Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 07; Vol. 121 (19), pp. e2318413121. Date of Electronic Publication: 2024 Apr 29.
DOI:	10.1073/pnas.2318413121
Abstrakt:	Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain ( MYH7 ) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 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 MYH7 WT/G256E 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 MYH7 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. Competing Interests: Competing interests statement:J.A.S. is a co-founder and consultant for Cytokinetics Inc. and owns stock in the company, which has a focus on therapeutic treatments for cardiomyopathies and other muscle diseases. D.B. is a consultant for Cytokinetics Inc.
Databáze:	MEDLINE
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