Journal article
Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
The Journal of clinical investigation, Vol.131(9), pp.1-16
05/03/2021
DOI: 10.1172/JCI145700
PMCID: PMC8087209
PMID: 33755597
Abstract
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca2+ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patients' biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC. Finally, we tested the therapeutic potential of the fast skeletal muscle troponin activator tirasemtiv in patients' myofibers and showed that the contractile dysfunction was repaired. Thus, our data reveal that pathogenic variants in TNNC2 cause congenital muscle disease, and they provide therapeutic angles to repair muscle contractility.
Details
- Title: Subtitle
- Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
- Creators
- Steven A Moore - University of IowaMartijn van de Locht - Vanderbilt UniversitySandra Donkervoort - National Institute of Neurological Disorders and StrokeJosine M de Winter - Vanderbilt UniversityStefan Conijn - Vanderbilt UniversityLeon Begthel - Vanderbilt UniversityBenno Kusters - Radboud University NijmegenPayam Mohassel - National Institute of Neurological Disorders and StrokeYing Hu - National Institute of Neurological Disorders and StrokeLivija Medne - Children's Hospital of PhiladelphiaColin Quinn - University of PennsylvaniaA Reghan Foley - National Institute of Neurological Disorders and StrokeGwimoon Seo - Florida State UniversityDarren T Hwee - Research and Early Development, Cytokinetics Inc., South San Francisco, California, USA.Fady I Malik - Research and Early Development, Cytokinetics Inc., South San Francisco, California, USA.Thomas Irving - Illinois Institute of TechnologyWeikang Ma - Illinois Institute of TechnologyHenk L Granzier - University of ArizonaErik-Jan Kamsteeg - University Medical CenterKalyan Immadisetty - Loyola University ChicagoPeter Kekenes-Huskey - Loyola University ChicagoJosé R Pinto - Florida State UniversityNicol Voermans - Radboud University NijmegenCarsten G Bönnemann - National Institute of Neurological Disorders and StrokeCoen Ac Ottenheijm - University of Arizona
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(9), pp.1-16
- DOI
- 10.1172/JCI145700
- PMID
- 33755597
- PMCID
- PMC8087209
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- P50 NS053672 / NINDS NIH HHS
- Language
- English
- Date published
- 05/03/2021
- Academic Unit
- Pathology
- Record Identifier
- 9984186499202771
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