PUBLICATION
Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy
- Authors
- Endo, Y., Groom, L., Wang, S.M., Pannia, E., Griffiths, N.W., Van Gennip, J.L.M., Ciruna, B., Laporte, J., Dirksen, R.T., Dowling, J.J.
- ID
- ZDB-PUB-231107-1
- Date
- 2023
- Source
- Human molecular genetics 33(3): 254-269 (Journal)
- Registered Authors
- Keywords
- Cav1.1, congenital myopathy, excitation contraction coupling, zebrafish
- MeSH Terms
-
- Animals
- Calcium Channels, L-Type*/genetics
- Calcium Channels, L-Type*/metabolism
- Humans
- Muscle, Skeletal/metabolism
- Muscular Diseases*/pathology
- Mutation
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins*/metabolism
- PubMed
- 37930228 Full text @ Hum. Mol. Genet.
Citation
Endo, Y., Groom, L., Wang, S.M., Pannia, E., Griffiths, N.W., Van Gennip, J.L.M., Ciruna, B., Laporte, J., Dirksen, R.T., Dowling, J.J. (2023) Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy. Human molecular genetics. 33(3):254-269.
Abstract
CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy is the lack of a suitable animal model that phenocopies key aspects of the disease. To address this barrier, we generated knockouts of the two zebrafish CACNA1S paralogs, cacna1sa and cacna1sb. Double knockout fish exhibit severe weakness and early death, and are characterized by the absence of Cav1.1 α1 subunit expression, abnormal triad structure, and impaired excitation-contraction coupling, thus mirroring the severe form of human CACNA1S-related myopathy. A double mutant (cacna1sa homozygous, cacna1sb heterozygote) exhibits normal development, but displays reduced body size, abnormal facial structure, and cores on muscle pathologic examination, thus phenocopying the mild form of human CACNA1S-related myopathy. In summary, we generated and characterized the first cacna1s zebrafish loss-of-function mutants, and show them to be faithful models of severe and mild forms of human CACNA1S-related myopathy suitable for future mechanistic studies and therapy development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping