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March 10, 2009CirculationOpen Access

Cardiac Myosin-Binding Protein C Mutations and Hypertrophic Cardiomyopathy

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Why the study?

Do frameshift MYBPC3 mutations alter sarcomere protein composition and function in patients with familial hypertrophic cardiomyopathy?

Population

Cardiac samples from familial hypertrophic cardiomyopathy patients with MYBPC3 frameshift mutations and…

Comparison

Presence of MYBPC3 frameshift mutations vs Nonfailing donor cardiac samples

Design

Preclinical

Key result

Frameshift MYBPC3 mutations caused haploinsufficiency and reduced maximal force-generating capacity of cardiomyocytes (20.2 vs 34.5 kN/m2) compared with nonfailing donors.

Authors

SDSabine J. van DijkDDDennis DooijesCRCristobal G. dos Remedios

Discussion

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Overview

Suggests contractile impairment in MYBPC3 models; leaves open human relevance and therapeutic targeting.

Key Points

  • To investigate whether sarcomeric protein composition, phosphorylation status, and contractile function are altered in familial hypertrophic cardiomyopathy patients carrying MYBPC3 frameshift mutations.
  • Analyzed human cardiac tissue samples from MYBPC3 frameshift mutation carriers (c.2373dupG, n=7; c.2864_2865delCT, n=4) compared to nonfailing donor controls (n=13).
  • Assessed protein expression and phosphorylation via Western blotting, and evaluated force-calcium relationships in isolated Triton-permeabilized cardiomyocytes with and without exogenous protein kinase A treatment.
  • Cardiac tissue from MYBPC3 mutant carriers exhibited a 33±5% decrease in cMyBP-C protein expression without truncated protein expression, accompanied by an 84±5% decrease in cardiac troponin I phosphorylation.
  • Maximal isometric force was reduced in MYBPC3 mutant cardiomyocytes (20.2±2.7 kN/m²) compared with donors (34.5±1.1 kN/m²), alongside increased Ca2+ sensitivity (pCa50 = 5.62±0.04 vs 5.54±0.02).
  • Exogenous protein kinase A treatment normalized Ca2+ sensitivity between MYBPC3 mutants (pCa50 = 5.46±0.03) and donors (pCa50 = 5.48±0.02) but did not rescue the deficit in maximal force generation.

Study Design

Type

Observational (n=24)

Structured PICO

Do frameshift MYBPC3 mutations alter sarcomere protein composition and function in patients with familial hypertrophic cardiomyopathy?

P
Population
Cardiac samples from familial hypertrophic cardiomyopathy patients with MYBPC3 frameshift mutations (c.2373dupG, n=7; c.2864_2865delCT, n=4) and nonfailing donors (n=13).
I
Intervention
Presence of MYBPC3 frameshift mutations
C
Comparator
Nonfailing donor cardiac samples
O
Outcome
Protein composition (cMyBP-C expression, phosphorylation status of cMyBP-C and cardiac troponin I) and sarcomere function (maximal force per cross-sectional area, Ca2+ sensitivity)surrogate

Main Result

Absolute Event Rate: 20.2% vs 34.5%

Frameshift MYBPC3 mutations cause haploinsufficiency and deranged phosphorylation of contractile proteins, leading to reduced maximal force and enhanced Ca2+ sensitivity in cardiomyocytes.

Cite This Study

Dijk et al. (2009) conducted an observational in Familial hypertrophic cardiomyopathy (n=24). MYBPC3 frameshift mutations vs. Nonfailing donors was evaluated on Maximal force per cross-sectional area of myocytes (kN/m2). Frameshift MYBPC3 mutations caused haploinsufficiency and reduced maximal force-generating capacity of cardiomyocytes (20.2 vs 34.5 kN/m2) compared with nonfailing donors.

synapsesocial.com/papers/6a0baa2da4798427da6dd08ehttps://doi.org/10.1161/circulationaha.108.838672
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