ArticleThe Journal of clinical investigation2021
Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Characterization and cellularity of myofibers during early development of Magalobrama amblycephala.Fish physiology and biochemistry · 2026Article
- Expanding the spectrum ofJournal of neuromuscular diseases · 2025Article
- Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.The Journal of physiology · 2025Article
- MYL1-Related Congenital Myopathy: Clinical, Genetic and Pathological Insights.Neuropathology and applied neurobiology · 2025Article
- Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2.International journal of molecular sciences · 2023Article
- RNA-Seq Reveals Sex Differences in Gene Expression during Peripheral Neuropathic Inflammation and in Pain Relief from a COX-2 Inhibiting Theranostic Nanoemulsion.International journal of molecular sciences · 2023Article
- Small Angle X-ray Diffraction as a Tool for Structural Characterization of Muscle Disease.International journal of molecular sciences · 2022Review
- Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel.Computational and structural biotechnology journal · 2022Article
- Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics.International journal of molecular sciences · 2021Review
- Structural Changes beyond the EF-Hand Contribute to Apparent Calcium Binding Affinities: Insights from Parvalbumins.The journal of physical chemistry. B · 2021Article
- Troponin Variants as Markers of Skeletal Muscle Health and Diseases.Frontiers in physiology · 2021Review
Corrections and comments
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Authors and funding
25 authors at 11 institutions in 2 countries.
Funding
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.
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