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A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C
Tyler R Reinoso1, Maicon Landim-Vieira2, Yun Shi1
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306, USA.
Insights
Familial cardiomyopathy is a heart muscle disease caused by inherited TNNC1 gene variants. This study maps these variants and protein modifications, revealing their widespread distribution and impact on cardiac function.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Biochemistry
Background:
- Familial cardiomyopathy encompasses inherited heart muscle diseases with diverse phenotypes, including hypertrophic (HCM), dilated (DCM), and left ventricular non-compaction (LVNC) cardiomyopathies.
- TNNC1, encoding cardiac troponin C (cTnC), is a sarcomeric gene linked to cardiomyopathies, often presenting with early onset and severe outcomes like sudden death or heart transplantation.
- Genetic variants in TNNC1 are associated with a higher burden of adverse events compared to variants in TNNT2 and TNNI3.
Purpose of the Study:
- To compile a comprehensive list of identified genetic variants and post-translational modifications (PTMs) in TNNC1 and cTnC.
- To structurally localize these variants and PTMs within the cardiac thin filament regulatory unit using cryo-EM data.
- To explore the functional implications of TNNC1 variants and cTnC PTMs in the context of cardiomyopathy and normal cardiac physiology.
Main Methods:
- Utilized databases (GnomAD, ClinVar, UniProt, PhosphoSitePlus) and literature review to identify TNNC1 variants and cTnC PTMs.
- Employed cryo-electron microscopy (cryo-EM) structural data to map the spatial distribution of variants and PTMs.
- Performed statistical analysis to assess the localization of cardiomyopathy-associated variants within cTnC structure.
Main Results:
- Compiled an extensive list of over 100 genetic variants in TNNC1, a significant number for its transcript size.
- Mapped identified variants and PTMs (acetylation, glycation, s-nitrosylation, phosphorylation) across the entire cTnC structure.
- Observed no statistically significant enrichment of cardiomyopathy-associated variants in specific structural regions like α-helices (p=0.72).
Conclusions:
- TNNC1 harbors a substantial number of variants, contributing to familial cardiomyopathies.
- The widespread distribution of variants and PTMs throughout cTnC suggests complex functional implications.
- Further investigation into TNNC1 variants and cTnC PTMs is crucial for understanding cardiac function and disease mechanisms.
Abstract:
Familial cardiomyopathy is an inherited disease that affects the structure and function of heart muscle and has an extreme range of phenotypes. Among the millions of affected individuals, patients with hypertrophic (HCM), dilated (DCM), or left ventricular non-compaction (LVNC) cardiomyopathy can experience morphologic changes of the heart which lead to sudden death in the most detrimental cases. TNNC1, the gene that codes for cardiac troponin C (cTnC), is a sarcomere gene associated with cardiomyopathies in which probands exhibit young age of presentation and high death, transplant or ventricular fibrillation events relative to TNNT2 and TNNI3 probands. Using GnomAD, ClinVar, UniProt and PhosphoSitePlus databases and published literature, an extensive list to date of identified genetic variants in TNNC1 and post-translational modifications (PTMs) in cTnC was compiled. Additionally, a recent cryo-EM structure of the cardiac thin filament regulatory unit was used to localize each functionally studied amino acid variant and each PTM (acetylation, glycation, s-nitrosylation, phosphorylation) in the structure of cTnC. TNNC1 has a large number of variants (> 100) relative to other genes of the same transcript size. Surprisingly, the mapped variant amino acids and PTMs are distributed throughout the cTnC structure. While many cardiomyopathy-associated variants are localized in α-helical regions of cTnC, this was not statistically significant χ2 (p = 0.72). Exploring the variants in TNNC1 and PTMs of cTnC in the contexts of cardiomyopathy association, physiological modulation and potential non-canonical roles provides insights into the normal function of cTnC along with the many facets of TNNC1 as a cardiomyopathic gene.
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