PUBLICATION
Loss of tropomodulin4 in the zebrafish mutant träge causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy
- Authors
- Berger, J., Tarakci, H., Berger, S., Li, M., Hall, T.E., Arner, A., Currie, P.D.
- ID
- ZDB-PUB-141008-5
- Date
- 2014
- Source
- Disease models & mechanisms 7(12): 1407-15 (Journal)
- Registered Authors
- Berger, Joachim, Berger, Silke, Currie, Peter D., Hall, Thomas, Tarakci, Hakan
- Keywords
- none
- MeSH Terms
-
- Neuromuscular Diseases/metabolism
- Tropomodulin/genetics*
- Tropomodulin/physiology*
- Genetic Linkage
- Animals, Genetically Modified
- PubMed
- 25288681 Full text @ Dis. Model. Mech.
Abstract
Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the 9 genes associated with the disease, 5 encode for components of striated muscle sarcomeres. In a genetic zebrafish screen the mutant träge (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganized and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of träge combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, while actin monomers polymerise to form thin filaments in skeletal muscle of tmod4(trg) mutants, thin filaments often appeared dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion, and early death. Myofibril of tmod4(trg) mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones, and electron-dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods together with the reactivity of rods with phalloidin and an antibody against actinin is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4(trg) mutants. While tropomodulin4 has not been associated with myopathy, the presented results make TMOD4 a novel candidate for unresolved nemaline myopathies and suggest the tmod4(trg) mutant as a valuable tool to study human muscle disorders.
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Phenotype
Mutations / Transgenics
Human Disease / Model
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Fish
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