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Updated: Jun 27, 2025
03:45
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
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Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated
Soah Lee1,2,3, Alison S Vander Roest4,5, Cheavar A Blair6,7
1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
Summary
The MYH7 G256E mutation causes hypercontractile myosin function, leading to early cardiac changes in hypertrophic cardiomyopathy. This study reveals a multiscale platform to assess gene variant pathogenicity in cardiovascular diseases.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Biophysics
Background:
- Determining pathogenicity of hypertrophic cardiomyopathy (HCM)-associated MYH7 mutations is challenging due to variable penetrance.
- The MYH7 G256E mutation is linked to HCM but its early pathogenic mechanisms remain unclear.
Purpose of the Study:
- Investigate early pathogenic effects of the MYH7 G256E mutation on myosin function.
- Hypothesize that G256E alters myosin biomechanics, triggering cellular adaptations and hypertrophy.
- Characterize multiscale effects of G256E on the contractile apparatus, gene regulation, and metabolism.
Main Methods:
- Developed a collaborative pipeline to analyze myosin function from protein to tissue levels.
- Utilized gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
- Performed single-cell transcriptomic and metabolic profiling.
Main Results:
- G256E mutation disrupts the S1 head transducer region, increasing available myosin heads for contraction.
- Myofibrils and hiPSC-CMs from G256E models showed greater and faster tension development (hypercontractility).
- Upregulated mitochondrial genes and increased respiration indicated early bioenergetic alterations.
Conclusions:
- MYH7 G256E mutation causes a consistent hypercontractile myosin phenotype across multiple scales.
- This hypercontractility is a primary consequence, highlighting the variant's pathogenicity.
- The multiscale platform effectively evaluates gene variant pathogenicity and early cellular/tissue consequences for cardiovascular diseases.
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