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.
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
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping