Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
Martijn van de Locht, … , Carsten G. Bönnemann, Coen A.C. Ottenheijm
Martijn van de Locht, … , Carsten G. Bönnemann, Coen A.C. Ottenheijm
Published March 23, 2021
Citation Information: J Clin Invest. 2021;131(9):e145700. https://doi.org/10.1172/JCI145700.
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Research Article Genetics Muscle biology

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium

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.

Authors

Martijn van de Locht, Sandra Donkervoort, Josine M. de Winter, Stefan Conijn, Leon Begthel, Benno Kusters, Payam Mohassel, Ying Hu, Livija Medne, Colin Quinn, Steven A. Moore, A. Reghan Foley, Gwimoon Seo, Darren T. Hwee, Fady I. Malik, Thomas Irving, Weikang Ma, Henk L. Granzier, Erik-Jan Kamsteeg, Kalyan Immadisetty, Peter Kekenes-Huskey, José R. Pinto, Nicol Voermans, Carsten G. Bönnemann, Coen A.C. Ottenheijm

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Figure 2

Pedigrees and clinical description of F1:P1 and F2:P1.

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Pedigrees and clinical description of F1:P1 and F2:P1. (A) Pedigree of f...
(A) Pedigree of family 1 showing multiple affected relatives in different generations, consistent with autosomal dominant inheritance. The + and – symbols in parentheses indicate positive and negative for the TNNC2 c.100G>T; p.D34Y missense variant by Sanger sequencing. Circles indicate female, squares indicate male, clinically affected relatives are shaded green, and unaffected relatives are unfilled white. (B) Left: Muscle MRI imaging of F1:P1. T1-axial images of the lower extremities show mild, focal fatty infiltration of different muscles in a patchy and heterogeneous pattern (arrows). Paraspinal muscles are significantly affected in F1:P1 (top left, arrowheads). Proximal thigh muscles (middle left) are more affected than lower leg muscles (bottom left). Right: Photograph of F1:P1 at age 6 weeks with hypotonia and lower-extremity weakness (top right) and at age 26 years with contractures of the long finger flexors (bottom right). (C) Pedigree of family 2. (D) Photograph of F2:P1 as an infant indicating weakness in the facial muscles (top left) and at age 19 years with normal muscle mass and retrognathia. (E) Visualization of muscle weakness using MuscleViz (https://muscleviz.github.io), based on the MRC scores (59).