Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics

Trisha Tucholski, Wenxuan Cai, Zachery R. Gregorich, Elizabeth F. Bayne, Stanford D. Mitchell, Sean J. McIlwain, Willem J. de Lange, Max Wrobbel, Hannah Karp, Zachary Hite, Petr G. Vikhorev, Steven B. Marston, Sean Lal, Amy Li, Cristobal dos Remedios, Takushi Kohmoto, Joshua Hermsen, J. Carter Ralphe, Timothy J. Kamp, Richard L. MossYing Ge

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. Although the genetic cause of HCM has been linked to mutations in genes encoding sarcomeric proteins, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited. Moreover, how mutations in different sarcomeric proteins can result in highly similar clinical phenotypes remains unknown. Posttranslational modifications (PTMs) and alternative splicing regulate the function of sarcomeric proteins; hence, it is critical to study HCM at the level of proteoforms to gain insights into the mechanisms underlying HCM. Herein, we employed high-resolution mass spectrometry-based top-down proteomics to comprehensively characterize sarcomeric proteoforms in septal myectomy tissues from HCM patients exhibiting severe outflow track obstruction (n = 16) compared to nonfailing donor hearts (n = 16). We observed a complex landscape of sarcomeric proteoforms arising from combinatorial PTMs, alternative splicing, and genetic variation in HCM. A coordinated decrease of phosphorylation in important myofilament and Z-disk proteins with a linear correlation suggests PTM cross-talk in the sarcomere and dysregulation of protein kinase A pathways in HCM. Strikingly, we discovered that the sarcomeric proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably consistent, regardless of the underlying HCM-causing mutations. This study suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct genotype, which underscores the importance of molecular characterization of HCM phenotype and presents an opportunity to identify broad-spectrum treatments to mitigate the most severe manifestations of this genetically heterogenous disease.

Original languageEnglish
Pages (from-to)24691-24700
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number40
DOIs
Publication statusPublished - 6 Oct 2020
Externally publishedYes

Keywords

  • Hypertrophic cardiomyopathy
  • Phosphorylation
  • Posttranslational modifications
  • Proteoform
  • Top-down proteomics

Fingerprint

Dive into the research topics of 'Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics'. Together they form a unique fingerprint.

Cite this