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Publications Abstracts
Chambers,
S. P., Dodd, A., Overall, R., Sirey, T., Lam, L.T.,
Morris, G.E., and Love, D. R. (2001). Dystrophin in Adult Zebrafish
Muscle. Biochemical and Biophysical Research Communications
286, 478–483
Mutations in the human dystrophin gene are implicated in the fatal
muscle wasting disease Duchenne Muscular Dystrophy (DMD). This gene
expresses a sarcolemmal-associated protein that is evolutionarily
conserved, underpinning its important role in the architecture of
muscle. In terms of DMD modelling, the mouse has served as a suitable
vertebrate species but the pathophysiology of the disease in the
mouse does not entirely mimic human DMD. We have examined the zebrafish
in order to expand the repertoire of vertebrate species for muscle
disease modelling, and to dissect further the functional interactions
of dystrophin. We report here the identification of an apparent
zebrafish orthologue of the human dystrophin gene that expresses
a 400-kDa protein that is localised to the muscle membrane surface.
These data suggest that the zebrafish may prove to be a beneficial
vertebrate model to examine the role and functional interactions
of dystrophin in disease and development.
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Chambers,
S. P., Anderson, L. V., Maguire, G. M., Dodd, A.,
and Love, D. R. (2003). Sarcoglycans of the zebrafish: orthology
and localization to the sarcolemma and myosepta of muscle. Biochem
Biophys Res Commun 303, 488-495.
The zebrafish is an established model of vertebrate development
and is also receiving increasing attention in terms of human disease
modelling. In order to provide experimental support to realize this
modelling potential, we report here the identification of apparent
orthologues of many critical members of the dystrophin-associated
glycoprotein complex (DGC) that have been implicated in a diverse
range of neuromuscular disorders. In addition, immunohistochemical
studies show the localization of the DGC to the sarcolemma of adult
zebrafish muscle and in particular the myosepta. Together, these
data suggest that the DGC in adult zebrafish may play a highly conserved
functional role in muscle architecture that, when disrupted, could
offer insight into human neuromuscular disease processes.
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Dodd,
A., Rowland, S.A., Hawkes,
S.L.J., Kennedy, M.A., and Love, D.R. (1997). Mutations in the Adrenoleukodystrophy
Gene. HUMAN MUTATION 9:500-511
Adrenoleukodystrophy (ALD) is a peroxisomal disorder that commonly
manifests as demyelination of the central nervous system (CNS).
The isolation of the ALD gene by positional cloning has led to the
identification of a variety of mutations in the ALD gene. One hundred
and ten mutations have been identified to date, of which approximately
50% are missense mutations. While rapid DNA-based diagnoses of ALD
is now possible, there appears to be no simple correlation between
genotype and phenotype.
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Dodd,
A., Curtis, P. M., Williams,
L. C., and Love, D. R. (2000). Zebrafish: bridging the gap between
development and disease. Hum Mol Genet 9, 2443-2449.
The zebrafish has been the model of choice amongst developmental
biologists for many years. This small freshwater species offers
many advantages to the study of organ and tissue development that
are not provided by other model systems. Against this background,
modern molecular genetic approaches are being applied to expand
the physical and genetic mapping of the zebrafish genome. These
approaches complement the large-scale mutagenic screens that have
led to the isolation of mutant phenotypes. Some of the phenotypes
have been found to resemble human disease states, while mapping
and sequencing data have revealed zebrafish genes with significant
homology to human disease-causing genes. It is the realization that
the zebrafish offers an amenable system for understanding disease,
as opposed to development, that underpins this review. The adventitious
identification of disease phenotypes amongst zebrafish mutants and
the impotant area of delibrate disease modelling using transgenesis
and gene targeting should lead to a better application of the zebrafish
as a vertebrate model of human diseases.
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Dodd,
A., Chambers, S. P., and Love,
D. R. (2004). Short interfering RNA-mediated gene targeting in the
zebrafish. FEBS Lett 561, 89-93.
Short interfering RNAs (siRNAs) have proved to be a useful tool
in studying gene function in plants, invertebrates and mammalian
systems. Here we report the use of siRNAs for targeting the zebra¢sh
dystrophin gene. This study demonstrates the e/cacy of siRNA-based
gene silencing in this vertebrate model species, and illustrates
the potential of this approach for determining the roles of multiple
protein products expressed by a single gene during the early stages
of development. In addition this study illustrates the usefulness
of zebrafish as a model for muscle disease, and highlights the potential
of siRNAbased gene targeting for disease analysis in this model
organism.
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