We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.
- Authors
Donkervoort, Sandra; van de Locht, Martijn; Ronchi, Dario; Reunert, Janine; McLean, Catriona A.; Zaki, Maha; Orbach, Rotem; de Winter, Josine M.; Conijn, Stefan; Hoomoedt, Daan; Neto, Osorio Lopes Abath; Magri, Francesca; Viaene, Angela N.; Foley, A. Reghan; Gorokhova, Svetlana; Bolduc, Véronique; Hu, Ying; Acquaye, Nicole; Napoli, Laura; Park, Julien H.
- Abstract
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 of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca2+], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism. Editor's summary: Although variants in TNNI2, encoding the fast-twitch isoform of troponin I, are a rare cause of disease in humans, variants in TNNI1, encoding the slow-twitch isoform of troponin I, have not been thoroughly investigated. Here, Donkervoort and colleagues identified five families with disease-causing variants in TNNI1. Three families carried recessive loss-of-function variants resulting in progressive muscle weakness, whereas two families carried dominant gain-of-function variants resulting in muscle cramping and myalgias. Functional studies on muscle biopsy samples revealed that sarcomeres carrying the loss-of-function variant p.R14H could be treated with a slow skeletal muscle troponin activator to reverse the observed contractile deficit, whereas sarcomeres carrying the gain-of-function p.R174Q variant were amenable to myosin inhibitor mavacamten, suggesting potential treatments for these patients carrying these TNNI1 variants. —Melissa L. Norton
- Subjects
MUSCLE diseases; NEMALINE myopathy; ARTHROGRYPOSIS; TROPONIN I; MUSCLE weakness; MUSCLE contraction; MOLECULAR dynamics
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 741, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adg2841