Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

Sandra Donkervoort, Martijn van de Locht, Dario Ronchi, Janine Reunert, Catriona A. McLean, Maha Zaki, Rotem Orbach, Josine M. de Winter, Stefan Conijn, Daan Hoomoedt, Osorio Lopes Abath Neto, Francesca Magri, Angela N. Viaene, A. Reghan Foley, Svetlana Gorokhova, Véronique Bolduc, Ying Hu, Nicole Acquaye, Laura Napoli, Julien H. ParkKalyan Immadisetty, Lee B. Miles, Mona Essawi, Salar McModie, Leonardo F. Ferreira, Simona Zanotti, Sarah B. Neuhaus, Livija Medne, Nagham ElBagoury, Kory R. Johnson, Yong Zhang, Nigel G. Laing, Mark R. Davis, Robert J. Bryson-Richardson, Darren T. Hwee, James J. Hartman, Fady I. Malik, Peter M. Kekenes-Huskey, Giacomo Pietro Comi, Wessam Sharaf-Eldin, Thorsten Marquardt, Gianina Ravenscroft, Carsten G. Bönnemann, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereadg2841
JournalScience translational medicine
Volume16
Issue number741
DOIs
StatePublished - 2024
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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