Hassoun, Roua, Budde, Heidi, Mannherz, Hans Georg, Lodi, Maria ORCID: 0000-0002-6533-770X, Fujita-Becker, Setsuko, Laser, Kai Thorsten, Gaertner, Anna ORCID: 0000-0001-6899-7693, Klingel, Karin, Moehner, Desiree, Stehle, Robert, Sultana, Innas, Schaaf, Thomas, Majchrzak, Mario, Krause, Verena, Herrmann, Christian, Nowaczyk, Marc M., Muegge, Andreas, Pfitzer, Gabriele, Schroder, Rasmus R., Hamdani, Nazha, Milting, Hendrik, Jaquet, Kornelia and Cimiotti, Diana (2021). De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents. Int. J. Mol. Sci., 22 (17). BASEL: MDPI. ISSN 1422-0067

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hassoun, RouaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, HeidiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannherz, Hans GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lodi, MariaUNSPECIFIEDorcid.org/0000-0002-6533-770XUNSPECIFIED
Fujita-Becker, SetsukoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laser, Kai ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaertner, AnnaUNSPECIFIEDorcid.org/0000-0001-6899-7693UNSPECIFIED
Klingel, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moehner, DesireeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stehle, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sultana, InnasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Majchrzak, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nowaczyk, Marc M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muegge, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfitzer, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroder, Rasmus R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamdani, NazhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milting, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaquet, KorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cimiotti, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-589170
DOI: 10.3390/ijms22179625
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 22
Number: 17
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HUMAN CARDIAC TROPONIN; PROTEIN-QUALITY CONTROL; HEAT-SHOCK PROTEINS; HYPERTROPHIC CARDIOMYOPATHY; PEDIATRIC CARDIOMYOPATHY; CALCIUM; MYOSIN; ACTIN; PHOSPHORYLATION; SUBFRAGMENT-1Multiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58917

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