LATE BREAKING NEWS ORAL PRESENTATION: LBO 1 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 never been implicated in muscle disease. Here, we report two families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations indicate that the pathomechanisms by which the variants cause muscle disease include disruption of the bindings 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, healthy 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.