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Published on: August 8, 2022
Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy
Adam S Helms1, Vi T Tang1, Thomas S O'Leary2
1Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Insights
Mutations in cardiac myosin binding protein C (MyBP-C) cause hypertrophic cardiomyopathy (HCM). Cardiomyocytes compensate for MYBPC3 mutations by slowing MyBP-C degradation, maintaining protein levels and normal function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Stem Cell Biology
Background:
- Mutations in MYBPC3 are the most common cause of hypertrophic cardiomyopathy (HCM).
- Most MYBPC3 mutations lead to premature termination codons (PTCs), causing RNA degradation and reduced MyBP-C protein.
- Reduced MyBP-C levels are not consistently observed in MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs).
Purpose of the Study:
- To investigate the early effects of MYBPC3 mutations on MyBP-C levels and cardiomyocyte function.
- To determine the mechanism of MyBP-C protein compensation in iPSCMs with MYBPC3 mutations.
- To explore potential therapeutic strategies for HCM based on MyBP-C regulation.
Main Methods:
- Utilized patient-derived and genome-engineered iPSCMs with various MYBPC3 mutations (frameshift, promoter, start site deletions).
- Compared heterozygous and homozygous mutant iPSCMs.
- Employed agnostic RNA-Seq analysis and stable isotope labeling to measure protein synthesis and degradation rates.
Main Results:
- Allelic loss of function, not just RNA degradation, is the primary consequence of MYBPC3 mutations causing PTCs.
- Despite reduced wild-type MYBPC3 mRNA, MyBP-C protein levels were compensated in heterozygous iPSCMs via a novel mechanism.
- Homozygous mutants showed contractile dysregulation, while heterozygous mutants maintained normal contractile function.
- Differential gene expression was primarily observed in protein folding pathways.
- Compensated MyBP-C levels resulted from reduced synthesis coupled with significantly slower degradation rates.
Conclusions:
- Cardiomyocytes possess an innate compensatory mechanism to maintain MyBP-C stoichiometry despite MYBPC3 allelic loss.
- This compensation involves a reduction in MyBP-C synthesis and a slower degradation rate.
- Targeting MyBP-C degradation could be a novel therapeutic approach for HCM, acting upstream of contractile dysfunction.
Abstract:
Mutations in cardiac myosin binding protein C (MyBP-C, encoded by MYBPC3) are the most common cause of hypertrophic cardiomyopathy (HCM). Most MYBPC3 mutations result in premature termination codons (PTCs) that cause RNA degradation and a reduction of MyBP-C in HCM patient hearts. However, a reduction in MyBP-C has not been consistently observed in MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs). To determine early MYBPC3 mutation effects, we used patient and genome-engineered iPSCMs. iPSCMs with frameshift mutations were compared with iPSCMs with MYBPC3 promoter and translational start site deletions, revealing that allelic loss of function is the primary inciting consequence of mutations causing PTCs. Despite a reduction in wild-type mRNA in all heterozygous iPSCMs, no reduction in MyBP-C protein was observed, indicating protein-level compensation through what we believe is a previously uncharacterized mechanism. Although homozygous mutant iPSCMs exhibited contractile dysregulation, heterozygous mutant iPSCMs had normal contractile function in the context of compensated MyBP-C levels. Agnostic RNA-Seq analysis revealed differential expression in genes involved in protein folding as the only dysregulated gene set. To determine how MYBPC3-mutant iPSCMs achieve compensated MyBP-C levels, sarcomeric protein synthesis and degradation were measured with stable isotope labeling. Heterozygous mutant iPSCMs showed reduced MyBP-C synthesis rates but a slower rate of MyBP-C degradation. These findings indicate that cardiomyocytes have an innate capacity to attain normal MyBP-C stoichiometry despite MYBPC3 allelic loss of function due to truncating mutations. Modulating MyBP-C degradation to maintain MyBP-C protein levels may be a novel treatment approach upstream of contractile dysfunction for HCM.
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