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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by

Trisha Tucholski1, Wenxuan Cai2,3, Zachery R Gregorich3

  • 1Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706.

Proceedings of the National Academy of Sciences of the United States of America
|September 24, 2020
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) is a heritable heart disease. Despite genetic diversity, severe HCM shows consistent proteoform alterations, suggesting a common molecular pathway for this complex condition.

Area of Science:

  • Cardiovascular Medicine
  • Proteomics
  • Genetics

Background:

  • Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often caused by sarcomeric protein gene mutations.
  • Predicting clinical outcomes and understanding phenotype similarities despite diverse mutations in HCM remains challenging.
  • Posttranslational modifications (PTMs) and alternative splicing significantly impact sarcomeric protein function, necessitating proteoform-level investigation in HCM.

Purpose of the Study:

  • To comprehensively characterize sarcomeric proteoforms in HCM patients with severe outflow tract obstruction.
  • To investigate the role of PTMs, alternative splicing, and genetic variations in HCM pathogenesis.
  • To determine if HCM proteoform alterations are consistent across different genetic mutations.

Main Methods:

  • High-resolution mass spectrometry-based top-down proteomics was utilized.
  • Septal myectomy tissues from HCM patients (n=16) and nonfailing donor hearts (n=16) were analyzed.
  • Sarcomeric proteoforms were characterized, focusing on PTMs, alternative splicing, and genetic variations.

Main Results:

  • A complex landscape of sarcomeric proteoforms, resulting from combinatorial PTMs, alternative splicing, and genetic variation, was observed in HCM.
  • A coordinated decrease in phosphorylation of myofilament and Z-disk proteins suggests PTM cross-talk and dysregulated protein kinase A pathways.
  • Remarkably consistent sarcomeric proteoform alterations were found in HCM myocardium, irrespective of the underlying genetic mutations.

Conclusions:

  • Severe HCM manifestations converge at the proteoform level, despite distinct genotypes.
  • This molecular convergence highlights the importance of characterizing the HCM phenotype at the proteoform level.
  • Identifying common proteoform alterations offers potential for developing broad-spectrum treatments for genetically diverse HCM.

Keywords:
hypertrophic cardiomyopathyphosphorylationposttranslational modificationsproteoformtop-down proteomics

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