PUBLICATION
Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease
- Authors
- Donkervoort, S., van de Locht, M., Ronchi, D., Reunert, J., McLean, C.A., Zaki, M., Orbach, R., de Winter, J.M., Conijn, S., Hoomoedt, D., Neto, O.L.A., Magri, F., Viaene, A.N., Foley, A.R., Gorokhova, S., Bolduc, V., Hu, Y., Acquaye, N., Napoli, L., Park, J.H., Immadisetty, K., Miles, L.B., Essawi, M., McModie, S., Ferreira, L.F., Zanotti, S., Neuhaus, S.B., Medne, L., ElBagoury, N., Johnson, K.R., Zhang, Y., Laing, N.G., Davis, M.R., Bryson-Richardson, R.J., Hwee, D.T., Hartman, J.J., Malik, F.I., Kekenes-Huskey, P.M., Comi, G.P., Sharaf-Eldin, W., Marquardt, T., Ravenscroft, G., Bönnemann, C.G., Ottenheijm, C.A.C.
- ID
- ZDB-PUB-240404-4
- Date
- 2024
- Source
- Science Translational Medicine 16: eadg2841eadg2841 (Journal)
- Registered Authors
- Bryson-Richardson, Robert, Miles, Lee
- Keywords
- none
- MeSH Terms
-
- Animals
- Calcium/metabolism
- Humans
- Muscle Contraction
- Muscle, Skeletal/metabolism
- Muscular Diseases*/genetics
- Sarcomeres*/metabolism
- Troponin I/genetics
- Troponin I/metabolism
- Zebrafish/metabolism
- PubMed
- 38569017 Full text @ Sci. Transl. Med.
Citation
Donkervoort, S., van de Locht, M., Ronchi, D., Reunert, J., McLean, C.A., Zaki, M., Orbach, R., de Winter, J.M., Conijn, S., Hoomoedt, D., Neto, O.L.A., Magri, F., Viaene, A.N., Foley, A.R., Gorokhova, S., Bolduc, V., Hu, Y., Acquaye, N., Napoli, L., Park, J.H., Immadisetty, K., Miles, L.B., Essawi, M., McModie, S., Ferreira, L.F., Zanotti, S., Neuhaus, S.B., Medne, L., ElBagoury, N., Johnson, K.R., Zhang, Y., Laing, N.G., Davis, M.R., Bryson-Richardson, R.J., Hwee, D.T., Hartman, J.J., Malik, F.I., Kekenes-Huskey, P.M., Comi, G.P., Sharaf-Eldin, W., Marquardt, T., Ravenscroft, G., Bönnemann, C.G., Ottenheijm, C.A.C. (2024) Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease. Science Translational Medicine. 16:eadg2841eadg2841.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping