PUBLICATION
Zebrafish and cellular models of SELENON-Congenital myopathy exhibit novel embryonic and metabolic phenotypes
- Authors
- Barraza-Flores, P., Moghadaszadeh, B., Lee, W., Isaac, B., Sun, L., Hickey, E.T., Rockowitz, S., Sliz, P., Beggs, A.H.
- ID
- ZDB-PUB-250317-3
- Date
- 2025
- Source
- Skeletal muscle 15: 77 (Journal)
- Registered Authors
- Beggs, Alan H.
- Keywords
- Congenital myopathy, Multiminicore myopathy, Rigid spine muscular dystrophy, Selenoprotein N, Zebrafish model
- MeSH Terms
-
- Myoblasts/metabolism
- Disease Models, Animal*
- Reactive Oxygen Species/metabolism
- Glutathione/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Muscular Diseases/genetics
- Muscular Diseases/metabolism
- Muscular Diseases/pathology
- Animals
- Phenotype*
- CRISPR-Cas Systems
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Animals, Genetically Modified
- Embryo, Nonmammalian/metabolism
- Selenoproteins*/genetics
- Selenoproteins*/metabolism
- PubMed
- 40087793 Full text @ Skelet Muscle
Citation
Barraza-Flores, P., Moghadaszadeh, B., Lee, W., Isaac, B., Sun, L., Hickey, E.T., Rockowitz, S., Sliz, P., Beggs, A.H. (2025) Zebrafish and cellular models of SELENON-Congenital myopathy exhibit novel embryonic and metabolic phenotypes. Skeletal muscle. 15:77.
Abstract
Background SELENON-Congenital Myopathy (SELENON-CM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology may be non-specific, but commonly includes multiminicores or a dystrophic pattern. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency cause SELENON-CM remain poorly understood. A hurdle is the lack of cellular and animal models that show easily assayable phenotypes.
Methods Using CRISPR-Cas9 we generated three zebrafish models of SELENON-CM, which were then studied by spontaneous coiling, hatching, and activity assays. We also performed selenon coexpression analysis using a single cell RNAseq zebrafish embryo-atlas. SelN-deficient myoblasts were generated and assayed for glutathione, reactive oxygen species, carbonylation, and nytrosylation levels. Finally, we tested Selenon-deficient myoblasts' metabolism using a Seahorse cell respirometer.
Results We report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression of selenon and genes involved in the glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit altered glutathione and redox homeostasis, as well as abnormal patterns of energy metabolism, suggesting roles for SelN in these functions.
Conclusions These data demonstrate a role for SelN in zebrafish early development and myoblast metabolism and provide a basis for cellular and animal model assays for SELENON-CM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping