De novo missense mutations in \(\it TNNC1\) and \(\it TNNI3\) causing severe infantile cardiomyopathy affect myofilament structure and function and are modulated by troponin targeting agents
- 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 \(\it TNNC1\) (\(\it {p.cTnC-G34S}\)) and \(\it TNNI3\) ((\(\it {p.cTnI-D127Y}\)) 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 inter-actions, 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.
Author: | Roua HassounGND, Heidi BuddeGND, Hans Georg MannherzGND, Mária LódiORCiDGND, Setsuko Fujita-BeckerGND, Kai Thorsten LaserORCiDGND, Anna Gärtner-RommelORCiDGND, Karin KlingelORCiDGND, Desirée Martha MöhnerGND, Robert StehleGND, Innas SultanaGND, Thomas SchaafORCiDGND, Mario MajchrzakGND, Verena KrauseGND, Christian HerrmannORCiDGND, Marc Michael NowaczykORCiDGND, Andreas MüggeORCiDGND, Gabriele PfitzerGND, Rasmus R. SchröderGND, Nazha HamdaniGND, Hendrik MiltingORCiDGND, Kornelia JaquetGND, Diana CimiottiORCiDGND |
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URN: | urn:nbn:de:hbz:294-89846 |
DOI: | https://doi.org/10.3390/ijms22179625 |
Parent Title (English): | International journal of molecular sciences |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2022/05/24 |
Date of first Publication: | 2021/09/06 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds EGCg; cardiomyopathy; contractile function; levosimendan; pediatric; skinned cardiomyocytes; skinned fibers; thin filaments; troponin mutation |
Volume: | 22 |
Issue: | Artikel 9625 |
First Page: | 9625-1 |
Last Page: | 9625-21 |
Note: | Article Processing Charge funded by the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Lehrstuhl für Biochemie der Pflanzen |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |