Mechanisms of Pathogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant R278C +/- During Development
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 recombin...
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Published in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
13.08.2023
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Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Working Paper/Pre-Print-1 content type line 23 |
ISSN: | 2692-8205 2692-8205 |
DOI: | 10.1101/2023.06.06.542948 |