PUBLICATION
Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy
- Authors
- Espinosa, K.G., Geissah, S., Groom, L., Volpatti, J., Scott, I.C., Dirksen, R.T., Zhao, M., Dowling, J.J.
- ID
- ZDB-PUB-220317-6
- Date
- 2022
- Source
- Disease models & mechanisms 15(5): (Journal)
- Registered Authors
- Dowling, Jim, Geissah, Salma, Scott, Ian, Volpatti, Jonathan, Zhao, Mo
- Keywords
- Centronuclear myopathy, Disease model, Excitation-contraction coupling, Muscle, SPEG, Zebrafish
- MeSH Terms
-
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Myopathies, Structural, Congenital*/genetics
- Myopathies, Structural, Congenital*/pathology
- Myosin-Light-Chain Kinase/genetics
- Myosin-Light-Chain Kinase/metabolism
- Animals
- Protein Serine-Threonine Kinases
- Humans
- Phenotype
- Muscle, Skeletal/pathology
- Mice
- Muscle Proteins/metabolism
- Dynamin II/genetics
- Dynamin II/metabolism
- Mutation
- PubMed
- 35293586 Full text @ Dis. Model. Mech.
Citation
Espinosa, K.G., Geissah, S., Groom, L., Volpatti, J., Scott, I.C., Dirksen, R.T., Zhao, M., Dowling, J.J. (2022) Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy. Disease models & mechanisms. 15(5):.
Abstract
Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation-contraction coupling (ECC). Bi-allelic autosomal recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb, and spega;spegb (speg-DKO) mutant lines. We demonstrate that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC, and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed desmin accumulation common to all CNM subtypes, and DNM2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping