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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Pathogenic MYBPC3 missense variants alter protein-protein interactions within the sarcomere
Insights
Pathogenic MYBPC3 missense variants in hypertrophic cardiomyopathy (HCM) do not reduce protein levels but alter interactions. These variants may enhance binding to thin filaments, suggesting new therapeutic targets for HCM.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Proteomics
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart disease often caused by MYBPC3 variants.
- Missense variants in MYBPC3's C3 and C6 subdomains are implicated in HCM, but their mechanism remains unclear.
- These variants normally localize to myofilaments, complicating understanding of their pathogenic effects.
Purpose of the Study:
- To investigate the mechanisms of MYBPC3 missense variants in HCM.
- To determine the prevalence of these variants in HCM patients.
- To analyze changes in MyBP-C interacting and proximity proteins caused by pathogenic missense variants.
Main Methods:
- Analysis of patient data from an international HCM registry.
- Quantification of total MyBP-C and mutant MyBP-C allelic fraction in human heart tissue.
- Flag-immunoprecipitation and proximity labeling mass spectrometry of wild-type and mutant MyBP-C.
Main Results:
- MYBPC3 missense variants in C3/C6 subdomains were found in 17.9% of HCM patients with MYBPC3 variants.
- Unlike truncating variants, missense variants did not decrease MyBP-C levels.
- Proximity labeling identified altered proximity of 789 proteins, with increased proximity to thin filament proteins.
Conclusions:
- Pathogenic MYBPC3 missense variants in C3/C6 subdomains are common in HCM patients.
- Mechanisms differ from haploinsufficiency, potentially involving enhanced protein-protein interactions with thin filaments.
- Findings suggest a gain-of-function mechanism driving HCM in these patients.
Background:
Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that leads to left ventricular hypertrophy, heart failure, and arrhythmias. Pathogenic missense variants in the gene myosin binding protein C ( MYBPC3) cluster within its internal subdomains C3 and C6. The protein (MyBP-C), carrying these missense variants, localizes normally to the myofilaments, leaving uncertainty regarding the mechanism(s) by which they cause HCM.
Methods:
We probed the molecular pathogenesis of these variants by analyzing (1) their prevalence in an international registry of patients with HCM, (2) total MyBP-C levels and the allelic fraction of mutant MyBP-C in human left ventricular heart tissue, and (3) performing flag-immunoprecipitation and proximity labeling mass spectrometry of wild-type MyBP-C and four pathogenic missense variants (Arg495Gln, Arg502Trp- C3, Trp792Arg, Arg810His- C6) to determine the change in MyBP-C interacting and proximity proteins induced by these variants.
Results:
We found that among patients with HCM who had any MYBPC3 pathogenic variant, 17.9% had a missense variant within the C3 or C6 subdomain. Unlike truncating variants, these C3 or C6 missense variants did not reduce MyBP-C content relative to myosin. The mutant allelic fraction of MyBP-C varied from 10.0-67.0% across samples. Flag-immunoprecipitation mass spectrometry identified 252 MyBP-C interacting proteins. Pathogenic missense variants disrupted 23 MyBP-C protein interactions, including lysosomal Ragulator-Rag complex proteins (RRAGA, RRAGC, LAMTOR4). Proximity labeling mass spectrometry was more sensitive, identifying 3,240 MyBP-C proximity proteins. Pathogenic missense variant(s) altered the proximity to MyBP-C of 789 proteins (69.4% increased and 30.5% decreased). Proteins that were increased in proximity to the missense MyBP-C were enriched for thin-filament proteins.
Conclusion:
Pathogenic MYBPC3 missense variants within the C3 and C6 subdomains are present in a substantial subset of patients with HCM. Our findings imply unique mechanisms of these variants distinct from haploinsufficiency, potentially driven by enhanced proximity to the thin filament within myofilaments.
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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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