PUBLICATION
Zebrafish mbnl mutants model physical and molecular phenotypes of myotonic dystrophy
- Authors
- Hinman, M.N., Richardson, J.I., Sockol, R.A., Aronson, E.D., Stednitz, S.J., Murray, K.N., Berglund, J.A., Guillemin, K.
- ID
- ZDB-PUB-210616-20
- Date
- 2021
- Source
- Disease models & mechanisms 14(6): (Journal)
- Registered Authors
- Guillemin, Karen
- Keywords
- MBNL1, MBNL2, MBNL3, Myotonic dystrophy, Zebrafish disease models
- Datasets
- GEO:GSE145270
- MeSH Terms
-
- Alternative Splicing
- Animals
- Disease Models, Animal
- Homozygote
- Mutation*
- Myotonic Dystrophy/genetics*
- Phenotype
- RNA-Binding Proteins/genetics*
- Zebrafish
- PubMed
- 34125183 Full text @ Dis. Model. Mech.
Citation
Hinman, M.N., Richardson, J.I., Sockol, R.A., Aronson, E.D., Stednitz, S.J., Murray, K.N., Berglund, J.A., Guillemin, K. (2021) Zebrafish mbnl mutants model physical and molecular phenotypes of myotonic dystrophy. Disease models & mechanisms. 14(6):.
Abstract
The muscleblind RNA-binding proteins (MBNL1, MBNL2 and MBNL3) are highly conserved across vertebrates and are important regulators of RNA alternative splicing. Loss of MBNL protein function through sequestration by CUG or CCUG RNA repeats is largely responsible for the phenotypes of the human genetic disorder myotonic dystrophy (DM). We generated the first stable zebrafish (Danio rerio) models of DM-associated MBNL loss of function through mutation of the three zebrafish mbnl genes. In contrast to mouse models, zebrafish double and triple homozygous mbnl mutants were viable to adulthood. Zebrafish mbnl mutants displayed disease-relevant physical phenotypes including decreased body size and impaired movement. They also exhibited widespread alternative splicing changes, including the misregulation of many DM-relevant exons. Physical and molecular phenotypes were more severe in compound mbnl mutants than in single mbnl mutants, suggesting partially redundant functions of Mbnl proteins. The high fecundity and larval optical transparency of this complete series of zebrafish mbnl mutants will make them useful for studying DM-related phenotypes and how individual Mbnl proteins contribute to them, and for testing potential therapeutics. This article has an associated First Person interview with the first author of the paper.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping