De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents.

Autor: Hassoun R; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Budde H; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Mannherz HG; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Anatomy and Molecular Embryology, Ruhr University Bochum, 44801 Bochum, Germany., Lódi M; Department of Neuroanatomy and Molecular Brain Research, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany., Fujita-Becker S; Cryoelectron Microscopy, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany., Laser KT; Centre for Congenital Heart Disease/Pediatric Cardiology, Heart and Diabetes Centre NRW, University Clinic of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany., Gärtner A; Heart and Diabetes Centre NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany., Klingel K; Institute for Pathology and Neuropathology, University Hospital Tuebingen, 72076 Tuebingen, Germany., Möhner D; Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany., Stehle R; Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany., Sultana I; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Schaaf T; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Majchrzak M; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Krause V; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Herrmann C; Department of Physical Chemistry I, Ruhr University Bochum, 44801 Bochum, Germany., Nowaczyk MM; Plant Biochemistry, Faculty of Biology and Biotechnology, Ruhr University Bochum, 44801 Bochum, Germany., Mügge A; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Pfitzer G; Institute of Vegetative Physiology, University of Cologne, 50931 Cologne, Germany., Schröder RR; Cryoelectron Microscopy, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany., Hamdani N; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Milting H; Heart and Diabetes Centre NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr University Bochum, 32545 Bad Oeynhausen, Germany., Jaquet K; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany., Cimiotti D; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, 44801 Bochum, Germany.; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, University Clinic of the Ruhr University Bochum, 44801 Bochum, Germany.; Department of Clinical Pharmacology, Ruhr University Bochum, 44801 Bochum, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Sep 06; Vol. 22 (17). Date of Electronic Publication: 2021 Sep 06.
DOI: 10.3390/ijms22179625
Abstrakt: Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient's myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.
Databáze: MEDLINE
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