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Lookup NU author(s): Dr Paul Thornhill, Dr David Bassett, Professor Hanns Lochmuller, Emerita Professor Katherine Bushby, Professor Volker StraubORCiD
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A number of muscular dystrophies are associated with the defective glycosylation of α-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 α-dystroglycan in these disorders leads to a failure of α-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 α-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. © The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
Author(s): Thornhill P, Bassett D, Lochmuller H, Bushby K, Straub V
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2008
Volume: 131
Issue: 6
Pages: 1551-1561
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/awn078
DOI: 10.1093/brain/awn078
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