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Proteomic and phosphoproteomic analyses of myectomy tissue reveals difference between sarcomeric and

Ramin Garmany1,2, J Martijn Bos2,3,4, Surendra Dasari5

  • 1Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of Medicine and the Mayo Clinic Medical Scientist Training Program, Rochester, MN, USA.

Scientific Reports
|September 1, 2023
PubMed

Insights

Genetic testing in hypertrophic cardiomyopathy (HCM) identifies patients with sarcomeric gene mutations (HCMSarc) who exhibit more severe disease. This study reveals enhanced proteomic and phosphoproteomic dysregulation in HCMSarc patients, potentially explaining their worse outcomes.

Area of Science:

  • Molecular Biology
  • Cardiovascular Genetics
  • Proteomics and Phosphoproteomics

Background:

  • Hypertrophic cardiomyopathy (HCM) is a genetically diverse heart muscle disease.
  • Approximately 50% of HCM cases lack identifiable genetic causes or remain genetically elusive.
  • Patients with genetically confirmed sarcomeric mutations (HCMSarc) often present with earlier onset and more severe disease compared to those with negative genetic tests (HCMNeg).

Purpose of the Study:

  • To investigate whether observed clinical differences between HCMSarc and HCMNeg are associated with distinct proteomic and phosphoproteomic profiles.
  • To identify specific molecular pathways dysregulated in genetically defined HCM subtypes.

Main Methods:

  • Quantitative proteomic and phosphoproteomic analysis using TMT-labeled mass spectrometry.
  • Comparison of protein expression and phosphorylation levels across 15 HCMSarc, 8 HCMNeg, and 7 control samples.
  • Bioinformatic pathway analysis to identify significantly altered biological processes.

Main Results:

  • Significant differential expression of 243 proteins and differential phosphorylation of 257 proteins between HCMSarc and HCMNeg groups.
  • Approximately 90% of the altered pathways were associated with disease mechanisms.
  • HCMSarc group exhibited more pronounced proteomic and phosphoproteomic alterations within these disease-related pathways.

Conclusions:

  • Genetically defined hypertrophic cardiomyopathy (HCMSarc) is characterized by enhanced proteomic and phosphoproteomic dysregulation compared to HCMNeg.
  • These molecular differences may underlie the more severe clinical phenotype observed in patients with sarcomeric genetic mutations.
  • Proteomic and phosphoproteomic profiling offers insights into genotype-phenotype correlations in hypertrophic cardiomyopathy.

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