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A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes

Diederik W D Kuster1, Suresh Govindan1, Tzvia I Springer2

  • 1From the Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois 60153, and.

The Journal of Biological Chemistry
|January 14, 2015
PubMed

Insights

A common hypertrophic cardiomyopathy (HCM) mutation in MYBPC3 disrupts cardiac myosin binding protein-C (cMyBP-C) C10 domain function. This impairs sarcomere integration and causes contractile dysfunction, explaining HCM development.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Genetic Basis of Heart Disease

Background:

  • Hypertrophic cardiomyopathy (HCM) is often caused by mutations in sarcomeric protein genes, particularly MYBPC3.
  • A prevalent 25-base pair deletion in MYBPC3 affects the C10 domain of cardiac myosin binding protein-C (cMyBP-C), but its molecular mechanism in HCM remains unclear.
  • Understanding how this mutation impacts cMyBP-C function is crucial for elucidating HCM pathogenesis.

Purpose of the Study:

  • To investigate the molecular mechanism by which the MYBPC3 C10 domain mutation (cMyBP-C(C10mut)) causes hypertrophic cardiomyopathy.
  • To evaluate the effect of cMyBP-C(C10mut) on protein localization, sarcomere function, and cardiomyocyte contractility in vitro.

Main Methods:

  • Adenoviral expression of wild-type (cMyBP-C(WT)) and mutant (cMyBP-C(C10mut)) cMyBP-C in cultured adult rat cardiomyocytes.
  • Immunofluorescence microscopy for protein localization within sarcomeres.
  • Subcellular fractionation to assess protein distribution.
  • Measurement of cardiomyocyte contractile function (fractional shortening, relaxation velocities) and calcium transients.
  • Co-sedimentation, protein cross-linking, and homology modeling to analyze protein interactions and structure.

Main Results:

  • cMyBP-C(C10mut) showed significantly reduced localization to the sarcomere C-zone compared to cMyBP-C(WT).
  • The mutation led to cMyBP-C(C10mut) accumulating in the soluble fraction with decreased myofilament association.
  • Cardiomyocytes expressing cMyBP-C(C10mut) exhibited impaired fractional shortening and relaxation velocities, without affecting Ca(2+) transients, indicating sarcomere dysfunction.
  • Binding assays confirmed that the C10 mutation disrupts the interaction between cMyBP-C and the myosin light meromyosin (LMM) region.
  • Structural modeling suggested significant perturbation of cMyBP-C(C10mut) structure, altering its myosin interaction.

Conclusions:

  • The HCM-associated MYBPC3 mutation impairs cMyBP-C integration into the sarcomere C-zone.
  • This defective localization and disrupted interaction with myosin LMM lead to cardiomyocyte contractile dysfunction.
  • Expression of cMyBP-C(C10mut) is sufficient to cause in vitro contractile deficits, providing a molecular basis for HCM pathogenesis.

Keywords:
CardiomyopathyContractile ProteinGenetic PolymorphismHeart FailureMuscle Physiology

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