Human Molecular Genetics Advance Access originally published online on July 14, 2004
Human Molecular Genetics 2004 13(18):1999-2010; doi:10.1093/hmg/ddh212
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency
1Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA, 2The Jackson Laboratory, Bar Harbor, ME 04609, USA, 3Department of Pathology, Children's Hospital, Boston, MA 02115, USA, 4Department of Pathology, Harvard Medical School, Boston, MA 02115, USA, 5Department of Neuropathology, Massachusetts General Hospital, MA 02114, USA and 6Center for Biologic Imaging, University of Pittsburgh, PA 15261, USA
Received April 22, 2004; Revised June 28, 2004; Accepted July 4, 2004
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. 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, in contrast to the latter group of animals, the 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 the A/J mice arose between the late 1970s and the early 1980s, and had become fixed in the production breeding stocks. Therefore, all studies involving the 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.
* To whom correspondence should be addressed at: Division of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610. Tel: +65 62221920; Fax: +65 63720161; Email: dmshmf{at}nccs.com.sg
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