Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics
| Autor: | Hannah Karp, J. Carter Ralphe, Zachery R. Gregorich, Willem J. de Lange, Timothy J. Kamp, Ying Ge, Elizabeth F. Bayne, Trisha Tucholski, Wenxuan Cai, Joshua L. Hermsen, Sean J. McIlwain, Amy Li, Steven B. Marston, Stanford D. Mitchell, Petr G. Vikhorev, Zachary Hite, Cristobal G. dos Remedios, Max Wrobbel, Sean Lal, Takushi Kohmoto, Richard L. Moss |
|---|---|
| Přispěvatelé: | British Heart Foundation |
| Rok vydání: | 2020 |
| Předmět: |
Proteomics
Sarcomeres Myofilament Medical Sciences Genotype macromolecular substances Biology top-down proteomics Mass Spectrometry medicine Humans cardiovascular diseases Gene Uncategorized Genetics Multidisciplinary phosphorylation Myocardium Alternative splicing Hypertrophic cardiomyopathy Proteins Cardiomyopathy Hypertrophic Biological Sciences hypertrophic cardiomyopathy medicine.disease Phenotype Septal myectomy proteoform Chemistry Physical Sciences cardiovascular system posttranslational modifications Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2006764117 |
| Popis: | Significance Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease and a leading cause of sudden cardiac death in young adults. HCM has been linked to mutations in genes encoding sarcomeric proteins, but how different mutations can result in a similar clinical phenotype is unknown. Analysis of surgical heart tissue samples from HCM patients with severe outflow track obstruction using high-resolution mass spectrometry–based top-down proteomics revealed a common pattern of altered sarcomeric proteoforms across HCM tissues compared to non-failing donor heart tissues. Our data suggest that common pathways are associated with clinical phenotypes in patients diagnosed with obstructive HCM, opening the door for the development of interventions that target the HCM phenotype rather than the individual sarcomeric gene mutation. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|