Brain Advance Access originally published online on May 13, 2008
Brain 2008 131(6):1551-1561; doi:10.1093/brain/awn078
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Developmental defects in a zebrafish model for muscular dystrophies associated with the loss of fukutin-related protein (FKRP)
Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 3BZ, UK
Correspondence to: Prof. Volker Straub, Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 3BZ, UK E-mail: volker.straub{at}ncl.ac.uk
A number of muscular dystrophies are associated with the defective glycosylation of 
-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 -dystroglycan in these disorders leads to a failure of -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 -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.
Key Words: dystroglycan; glycosylation; muscular dystrophy; zebrafish
Abbreviations: CMD, congenital muscular dystrophy; DGC, dystrophin–glycoprotein complex; ECM, extra-cellular matrix; FCMD, Fukuyama congenital muscular dystrophy; MEB, Muscle–Eye–Brain disease; WWS, Walker-Warburg syndrome.
Received October 17, 2007. Revised March 27, 2008. Accepted April 2, 2008.
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