A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C
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ORIGINAL PAPER
A comprehensive guide to genetic variants and post‑translational modifications of cardiac troponin C Tyler R. Reinoso1 · Maicon Landim‑Vieira2 · Yun Shi1 · Jamie R. Johnston2,6 · P. Bryant Chase1 · Michelle S. Parvatiyar3 · Andrew P. Landstrom4 · Jose R. Pinto2 · Hanna J. Tadros5 Received: 14 June 2020 / Accepted: 24 October 2020 © Springer Nature Switzerland AG 2020
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. Keywords Heart · TNNC1 · Cardiac troponin C (cTnC) · Cardiomyopathy · Genetic variant · Post-translational modification Tyler R. Reinoso and Maicon Landim-Vieira have contributed equally to this study. * P. Bryant Chase [email protected] * Hanna J. Tadros [email protected] 1
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA
2
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
3
Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32306, USA
4
Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC 27710, USA
5
Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA
6
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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