PUBLICATION
A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2 directed myogenesis
- Authors
- McAdow, J., Yang, S., Ou, T., Huang, G., Dobbs, M.B., Gurnett, C.A., Greenberg, M.J., Johnson, A.N.
- ID
- ZDB-PUB-220518-4
- Date
- 2022
- Source
- JCI insight 7(12): (Journal)
- Registered Authors
- Gurnett, Christina
- Keywords
- Molecular genetics, Movement disorders, Muscle, Muscle Biology
- MeSH Terms
-
- Animals
- Humans
- Mice
- Muscle Development/genetics
- Myopathies, Nemaline*/metabolism
- Myopathies, Structural, Congenital*/metabolism
- Tropomyosin/genetics
- Zebrafish
- PubMed
- 35579956 Full text @ JCI Insight
Citation
McAdow, J., Yang, S., Ou, T., Huang, G., Dobbs, M.B., Gurnett, C.A., Greenberg, M.J., Johnson, A.N. (2022) A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2 directed myogenesis. JCI insight. 7(12).
Abstract
Nemaline Myopathy (NM) is the most common congenital myopathy, characterized by extreme weakness of the respiratory, limb, and facial muscles. Pathogenic variants in Tropomyosin 2 (TPM2), which encodes a skeletal muscle specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders that include NM as well as Cap Myopathy, congenital fiber type disproportion, and distal arthrogryposis (DA). The in vivo pathomechanisms underlying TPM2-related disorders are unknown, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found four variants significantly affected muscle development and muscle function. Transient overexpression of the four variants also disrupted the morphogenesis of mouse myotubes in vitro, and negatively affected zebrafish muscle development in vivo. We used transient overexpression assays in zebrafish to characterize two novel TPM2 variants and one recurring variant that we identified in DA patients (V129A, E139K, A155T), and found these variants caused musculoskeletal defects similar to those of known pathogenic variants. The consistency of musculoskeletal phenotypes in our assays correlated with the severity of clinical phenotypes observed in our DA patients, suggesting disrupted myogenesis is a novel pathomechanism of TPM2 disorders, and that our myogenic assays can predict the clinical severity of TPM2 variants.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping