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Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through
Steven Marston1, O'Neal Copeland, Adam Jacques
1Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Oxford OX39DU, United Kingdom.
Insights
Hypertrophic cardiomyopathy caused by MYBPC3 mutations results from haploinsufficiency, not dominant negative effects. Reduced levels of cardiac myosin-binding protein-C (MyBP-C) in patients indicate this mechanism.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiomyopathy
Background:
- Most sarcomere gene mutations causing hypertrophic cardiomyopathy (HCM) result in dominant-negative proteins.
- Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein-C (MyBP-C), often produce truncated proteins, posing an exception.
Purpose of the Study:
- To investigate evidence of haploinsufficiency in HCM associated with MYBPC3 mutations.
- Comparison of left ventricular muscle from HCM patients and donor hearts.
Main Methods:
- Quantification of MyBP-C protein and mRNA levels using immunoblotting and RT-PCR.
- Analysis of 37 myectomy samples for MYBPC3 mutations (missense and premature termination).
Main Results:
- Seven of nine MYBPC3 mutations involved premature termination, and two were missense.
- No truncated MyBP-C peptides were detected in HCM tissue.
- Significantly reduced overall MyBP-C levels in myofibrils of patients with MYBPC3 mutations (truncation or missense) compared to controls.
Conclusions:
- Absence of detectable truncated MyBP-C suggests no dominant-negative effect.
- Lowered full-length MyBP-C levels in both truncation and missense MYBPC3 mutations strongly support haploinsufficiency as the disease mechanism.
Rationale:
Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the MYBPC3 gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins.
Objective:
We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by MYBPC3 mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts.
Methods And Results:
MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in MYBPC3: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation: 0.76+/-0.03 compared with 1.00+/-0.05 in donor and 1.01+/-0.06 in non-MYBPC3 mutant myectomies.
Conclusions:
The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient to cause the disease.
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