Mechanisms of Pathogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant R278C +/- During Development

• Published in: bioRxiv
• Main Authors: Shafaattalab, Sanam, Li, Alison Y, Jayousi, Farah, Maaref, Yasaman, Dababneh, Saif, Hamledari, Homa, Baygi, Dina Hosseini, Barszczewski, Tiffany, Ruprai, Balwinder, Jannati, Shayan, Nagalingam, Raghu, Cool, Austin M, Langa, Paulina, Chiao, Mu, Roston, Thomas, Solaro, R John, Sanatani, Shubhayan, Toepfer, Christopher, Lindert, Steffen, Lange, Philipp, Tibbits, Glen F
• Format: Journal Article
• Language: English
• Published: United States 13.08.2023
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.06.06.542948

Hypertrophic cardiomyopathy (HCM) is one of the most common heritable cardiovascular diseases and variants of (cardiac troponin T) are linked to increased risk of sudden cardiac arrest despite causing limited hypertrophy. In this study, a variant, R278C , was generated in both human cardiac recombinant/reconstituted thin filaments (hcRTF) and human- induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which the R278C variant affects cardiomyocytes at the proteomic and functional levels. The results of proteomics analysis showed a significant upregulation of markers of cardiac hypertrophy and remodeling in R278C vs. the isogenic control. Functional measurements showed that R278C variant enhances the myofilament sensitivity to Ca , increases the kinetics of contraction, and causes arrhythmia at frequencies >75 bpm. This study uniquely shows the profound impact of the R278C variant on the cardiomyocyte proteomic profile, cardiac electrical and contractile function in the early stages of cardiac development.