PUBLICATION
The zebrafish dag1 mutant: A novel genetic model for dystroglycanopathies
- Authors
- Gupta, V., Kawahara, G., Gundry, S.R., Chen, A.T., Lencer, W.I., Zhou, Y., Zon, L.I., Kunkel, L.M., and Beggs, A.H.
- ID
- ZDB-PUB-110214-7
- Date
- 2011
- Source
- Human molecular genetics 20(9): 1712-25 (Journal)
- Registered Authors
- Beggs, Alan H., Gupta, Vandana A, Kawahara, Genri, Kunkel, Louis M., Lencer, Wayne, Zhou, Yi, Zon, Leonard I.
- Keywords
- none
- MeSH Terms
-
- Animals
- Base Sequence
- Disease Models, Animal*
- Dystroglycans/genetics*
- Dystroglycans/metabolism
- Female
- Humans
- Male
- Molecular Sequence Data
- Motor Activity
- Muscle, Skeletal/metabolism
- Muscular Dystrophies/genetics*
- Muscular Dystrophies/metabolism
- Muscular Dystrophies/physiopathology
- Mutation, Missense*
- Point Mutation
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 21296866 Full text @ Hum. Mol. Genet.
Citation
Gupta, V., Kawahara, G., Gundry, S.R., Chen, A.T., Lencer, W.I., Zhou, Y., Zon, L.I., Kunkel, L.M., and Beggs, A.H. (2011) The zebrafish dag1 mutant: A novel genetic model for dystroglycanopathies. Human molecular genetics. 20(9):1712-25.
Abstract
In a forward genetic approach to identify novel genes for congenital muscle diseases, a zebrafish mutant, designated patchytail, was identified that exhibits degenerating muscle fibers with impaired motility behavior. Genetic mapping identified a genomic locus containing the zebrafish ortholog of the dystroglycan gene (DAG1). Patchytail fish contain a point mutation (c.1700T>A) in dag1, resulting in a missense change p.V567D. This change is associated with reduced transcripts and a complete absence of protein. Absence of α-dystroglycan and β-dystroglycan caused destabilization of dystroglycan complex resulting in membrane damages. Membrane damage was localized on the extracellular matrix at myosepta as well as basement membrane between adjacent myofibers. These studies also identified structural abnormalities in triads at 3 dpf of dystroglycan-deficient muscles significantly preceding sarcolemmal damage that becomes evident at 7 dpf. Immunofluorescence studies identified a subpopulation of dystroglycan that is expressed at t-tubules in normal skeletal muscles. In dag1-mutated fish, smaller and irregular shaped t-tubule vesicles, as well as highly disorganized terminal cisternae of sarcoplasmic reticulum, were common. In addition to skeletal muscle defects, dag1-mutated fish have brain abnormalities and ocular defects in posterior as well as anterior chambers. These phenotypes of dystroglycan-deficient fish are highly reminiscent of the phenotypes observed in the human conditions Muscle Eye and Brain disease (MEB) and Walker-Warburg Syndrome (WWS). This animal model will provide unique opportunities in the understanding of biological functions of dystroglycan in a wide range of dystroglycanopathies, as disruption of this gene in higher vertebrates results in early embryonic lethality.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping