TY - JOUR
T1 - Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
AU - van de Locht, Martijn
AU - Donkervoort, Sandra
AU - de Winter, Josine M.
AU - Conijn, Stefan
AU - Begthel, Leon
AU - Kusters, Benno
AU - Mohassel, Payam
AU - Hu, Ying
AU - Medne, Livija
AU - Quinn, Colin
AU - Moore, Steven A.
AU - Foley, A. Reghan
AU - Seo, Gwimoon
AU - Hwee, Darren T.
AU - Malik, Fady I.
AU - Irving, Thomas
AU - Ma, Weikang
AU - Granzier, Henk L.
AU - Kamsteeg, Erik-Jan
AU - Immadisetty, Kalyan
AU - Kekenes-Huskey, Peter
AU - Pinto, José R.
AU - Voermans, Nicol
AU - Bönnemann, Carsten G.
AU - Ottenheijm, Coen A. C.
N1 - Funding Information: We thank the families for participating in this study, and Christopher Mendoza and Gilberto (“Mike”) Averion for their help in the clinic. We also thank the NIH Intramural Sequencing Center for performing the exome sequencing. The Ottenheijm laboratory is supported by a ZonMW-VICI grant (number 91819613), H2020-MSCA-RISE-2014 (64568 “Muscle Stress Relief”), and a Muscle Dystrophy UK grant (16NEM-PG36-0111). JRP is supported by the NHLBI/NIH award HL128683. HLG is supported by NIAMS/NIH R01AR053897. Work in the Bönnemann laboratory is supported by intramural funds from NINDS/NIH. Exome sequencing was funded through the Clinical Center Genomics Opportunity (CCGO), which is sponsored by the National Human Genome Research Institute (NHGRI), the NIH Deputy Director for Intramural Research, and the NIH Clinical Center. PKH was supported by the Maximizing Investigators’ Research Award (MIRA) from NIGMS/NIH (R35GM124977) as well as supercomputer time from The Extreme Science and Engineering Discovery Environment (57). SAM is partially supported by the Iowa Wellstone Muscular Dystrophy Specialty Research Center (NINDS/NIH U54 NS053672). Publisher Copyright: Copyright: © 2021, American Society for Clinical Investigation. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105249329&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI145700
DO - https://doi.org/10.1172/JCI145700
M3 - Article
C2 - 33755597
SN - 0021-9738
VL - 131
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 9
M1 - e145700
ER -