PUBLICATION
Developmental defects in a zebrafish model for muscular dystrophies associated with the loss of fukutin-related protein (FKRP)
- Authors
- Thornhill, P., Bassett, D., Lochmüller, H., Bushby, K., and Straub, V.
- ID
- ZDB-PUB-080515-15
- Date
- 2008
- Source
- Brain : a journal of neurology 131(Pt 6): 1551-1561 (Journal)
- Registered Authors
- Bassett, David
- Keywords
- dystroglycan, glycosylation, muscular dystrophy, zebrafish
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Base Sequence
- Down-Regulation
- Dystroglycans/analysis
- Dystroglycans/metabolism
- Glycosylation
- Glycosyltransferases/genetics*
- Immunohistochemistry
- Laminin/analysis
- Laminin/metabolism
- Microscopy, Electron
- Models, Animal
- Molecular Sequence Data
- Muscle, Skeletal/chemistry
- Muscle, Skeletal/pathology*
- Muscle, Skeletal/physiopathology
- Muscular Dystrophies/genetics*
- Muscular Dystrophies/pathology*
- Muscular Dystrophies/physiopathology
- Oligonucleotides, Antisense/pharmacology*
- Zebrafish
- Zebrafish Proteins/genetics*
- PubMed
- 18477595 Full text @ Brain
Citation
Thornhill, P., Bassett, D., Lochmüller, H., Bushby, K., and Straub, V. (2008) Developmental defects in a zebrafish model for muscular dystrophies associated with the loss of fukutin-related protein (FKRP). Brain : a journal of neurology. 131(Pt 6):1551-1561.
Abstract
A number of muscular dystrophies are associated with the defective glycosylation of alpha-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy (FCMD), Muscle-Eye-Brain disease (MEB) and Walker-Warburg syndrome (WWS), which are associated with brain and eye abnormalities. The defective glycosylation of alpha-dystroglycan in these disorders leads to a failure of alpha-dystroglycan to bind to extra-cellular matrix components and previous attempts to model these disorders have shown that the generation of fukutin- and Pomt1-deficient knockout mice results in early embryonic lethality due to basement membrane defects. We have used the zebrafish as an animal model to investigate the pathological consequences of downregulating the expression of the putative glycosyltransferase gene fukutin-related protein (FKRP) on embryonic development. We have found that downregulating FKRP in the zebrafish results in embryos which develop a range of abnormalities reminiscent of the developmental defects observed in human muscular dystrophies associated with mutations in FKRP. FKRP morphant embryos showed a spectrum of phenotypic severity involving alterations in somitic structure and muscle fibre organization as well as defects in developing neuronal structures and eye morphology. The pathological phenotype was found to correlate with a reduction in alpha-dystroglycan glycosylation and reduced laminin binding. Further characterization of the developmental processes affected in FKRP morphant embryos may lead to a better understanding of the pathological spectrum observed in muscular dystrophies associated with mutations in the human FKRP gene.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping