Related Experiment Video
Updated: Jun 23, 2026
An Approach to Study Shape-Dependent Transcriptomics at a Single Cell Level
Published on: November 2, 2020
Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged
Sabine J van Dijk1, Dennis Dooijes, Cris dos Remedios
1Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Insights
Familial hypertrophic cardiomyopathy caused by MYBPC3 mutations leads to reduced cardiac myosin-binding protein C (cMyBP-C) expression and impaired cardiomyocyte contractility. This dysfunction results in decreased maximal force and altered calcium sensitivity.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Diseases
Background:
- Familial hypertrophic cardiomyopathy (FHC) is frequently caused by mutations in the MYBPC3 gene.
- MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a key sarcomeric protein.
- This study investigates sarcomere alterations in FHC patients with MYBPC3 frameshift mutations.
Purpose of the Study:
- To determine the impact of MYBPC3 frameshift mutations on sarcomere protein composition and function.
- To investigate alterations in cMyBP-C expression and phosphorylation.
- To assess cardiomyocyte contractility and calcium sensitivity in affected individuals.
Main Methods:
- Western blot analysis of cardiac samples from MYBPC3 mutant carriers and non-failing donors.
- Measurement of cMyBP-C and cardiac troponin I phosphorylation.
- Mechanically isolated Triton-permeabilized cardiomyocyte force measurements.
- Assessment of calcium (Ca2+) sensitivity and response to protein kinase A stimulation.
Main Results:
- MYBPC3 mutant carriers showed significantly reduced cMyBP-C expression (33%) but no truncated protein.
- Cardiac troponin I phosphorylation was markedly reduced (84%) in MYBPC3 mutants.
- Maximal force per area was decreased, and Ca2+ sensitivity was increased in MYBPC3 mutant cardiomyocytes.
- Protein kinase A stimulation did not restore maximal force but normalized Ca2+ sensitivity.
Conclusions:
- MYBPC3 frameshift mutations lead to haploinsufficiency and altered contractile protein phosphorylation.
- Reduced cMyBP-C expression and hypophosphorylation of troponin I contribute to impaired cardiomyocyte function.
- These molecular changes result in reduced maximal force-generating capacity and altered Ca2+ sensitivity in FHC.
Background:
Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)).
Methods And Results:
Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c.2373dupG, n=7; c.2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33+/-5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84+/-5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2+/-2.7 kN/m(2)) compared with donor (34.5+/-1.1 kN/m(2)). Moreover, Ca(2+) sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62+/-0.04) than in donor (pCa(50)=5.54+/-0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca(2+) sensitivity between MYBPC3(mut) (pCa(50)=5.46+/-0.03) and donor (pCa(50)=5.48+/-0.02).
Conclusions:
Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca(2+) sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction.
Related Concept Videos
01:17Pathophysiology of Heart Failure
01:29Heart Failure II: Pathophysiology
01:25Cardiomyopathy I: Introduction and Classification
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:29Cardiomyopathy V: Interprofessional Care