Human Molecular Genetics Advance Access published online on July 14, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh212
© 2004 by Oxford University Press
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1 Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Division of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore
* To whom correspondence should be addressed. E-mail: dmshmf{at}nccs.com.sg.
Limb girdle muscular dystrophy type 2B and Miyoshi myopathy are clinically distinct forms of muscular dystrophy that arise from defects in the dysferlin gene. Here, we report two novel lines of dysferlin-deficient mice obtained by (a) gene targeting and (b) identification of an inbred strain, A/J, bearing a retrotransposon insertion in the dysferlin gene. The mutations in these mice were located at the 3' and 5' ends of the dysferlin gene respectively. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathological and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx and caveolin-3 deficient mice. However, by contrast to the latter group of animals, dysferlin-deficient mice have an intact dystrophin glycoprotein complex and normal levels of caveolin-3. Our findings indicate that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies. We also show that the mutation in A/J mice arose between the late 1970s and early 1980s, and had become fixed in the production breeding stocks. Therefore, all studies involving A/J mice or mice derived from A/J, including recombinant inbred, recombinant congenic, and chromosome substitution strains, should take into account the dysferlin defect in these strains. These new dysferlin-deficient mice should be useful for elucidating the pathogenic pathway in dysferlinopathy and for developing therapeutic strategies.
Article
Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin-deficiency
2 The Jackson Laboratory, Bar Harbor, ME 04609, USA
3 Department of Pathology, Children's Hospital, Boston, MA 02115, USA
4 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
5 Department of Neuropathology, Massachusetts General Hospital, MA 02114, USA
6 Center for Biologic Imaging, University of Pittsburgh, PA 15261, USA
7 Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
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