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Updated: Jan 29, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy
Theresia Kraft1, Judith Montag2
1Molecular and Cell Physiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Insights
Hypertrophic cardiomyopathy (HCM) arises from sarcomeric protein mutations. This study reveals cell-to-cell variability in mutant MYH7-mRNA, driving contractile imbalance and HCM pathology.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease often caused by mutations in sarcomeric proteins, particularly ventricular myosin heavy chain (β-MyHC).
- The precise molecular mechanisms linking diverse mutations to the common HCM phenotype remain incompletely understood.
- A proposed mechanism involves mutation-induced alterations in myosin head states, such as the super-relaxed state (SRX), potentially leading to hypercontractility.
Purpose of the Study:
- To investigate the structural states of myosin and their role in HCM pathogenesis.
- To explore the concept of contractile imbalance as a unifying mechanism for HCM caused by sarcomeric protein mutations.
- To determine if cell-to-cell variability in mutant protein expression correlates with HCM pathology.
Main Methods:
- Analysis of myosin structural states in the context of weak binding cross-bridges and the interacting head motif.
- Assessment of contractile function variability at the single cardiomyocyte level within patient myocardium.
- Quantification of mutant MYH7-mRNA fraction and allelic imbalance using cell-to-cell analysis.
Main Results:
- HCM-associated mutations likely alter myosin force generation, potentially inhibiting the SRX state, leading to functional hyper- or hypocontractile changes.
- Significant cardiomyocyte contractile variability was observed in HCM patients, exceeding that of controls.
- This contractile variability was directly paralleled by a similarly high cell-to-cell variation in mutant MYH7-mRNA fraction, attributed to random, burst-like transcription.
Conclusions:
- Contractile imbalance, stemming from unequal fractions of mutated and wild-type proteins within cardiomyocytes, is a key driver of cardiomyocyte disarray and fibrosis in HCM.
- Random, burst-like gene transcription leads to cell-to-cell allelic imbalance, explaining the observed functional variability in HCM.
- This mechanism likely applies to HCM caused by mutations in various sarcomeric proteins, not just β-MyHC.
Abstract:
Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomeric proteins. Thirty to forty percent of identified mutations are found in the ventricular myosin heavy chain (β-MyHC). A common mechanism explaining how numerous mutations in several different proteins induce a similar HCM-phenotype is unclear. It was proposed that HCM-mutations cause hypercontractility, which for some mutations is thought to result from mutation-induced unlocking of myosin heads from a so-called super-relaxed state (SRX). The SRX was suggested to be related to the "interacting head motif," i.e., pairs of myosin heads folded back onto their S2-region. Here, we address these structural states of myosin in context of earlier work on weak binding cross-bridges. However, not all HCM-mutations cause hypercontractility and/or are involved in the interacting head motif. But most likely, all mutations alter the force generating mechanism, yet in different ways, possibly including inhibition of SRX. Such functional-hyper- and hypocontractile-changes are the basis of our previously proposed concept stating that contractile imbalance due to unequal fractions of mutated and wildtype protein among individual cardiomyocytes over time will induce cardiomyocyte disarray and fibrosis, hallmarks of HCM. Studying β-MyHC-mutations, we found substantial contractile variability from cardiomyocyte to cardiomyocyte within a patient's myocardium, much higher than in controls. This was paralleled by a similarly variable fraction of mutant MYH7-mRNA (cell-to-cell allelic imbalance), due to random, burst-like transcription, independent for mutant and wildtype MYH7-alleles. Evidence suggests that HCM-mutations in other sarcomeric proteins follow the same disease mechanism.
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