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Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease
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Edité par CCSD ; American Association for the Advancement of Science (AAAS) -
International audience. Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI- fast (TNNI2) and TnI- slow(TNNI1), are predominantly expressed in fast- and slow- twitch myofibers, respectively. TNNI2 variants are a rare cause ofarthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identifiedrecessive loss- of- function TNNI1 variants as well as dominant gain- of- function TNNI1 variants as a cause of muscledisease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelicTNNI1 variants (F1: p.R14H/c.190- 9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifestingwith early- onset progressive muscle weakness and rod formation on histology. We also identified two families with adominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifestingwith muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missensevariants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that theloss- of- function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reducedforce response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by aslow skeletal muscle troponin activator. In contrast, patient myofibers with the gain- of- function p.R174Q variantshowed an increased force to submaximal [Ca2+], which was reversed by the small- molecule drug mavacamten. Ourfindings demonstrated that TNNI1 variants can cause muscle disease with variant- specific pathomechanisms, manifestingas either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.
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