Document Detail

Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.
MedLine Citation:
PMID:  15254015     Owner:  NLM     Status:  MEDLINE    
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.
Mengfatt Ho; Cristina M Post; Leah R Donahue; Hart G W Lidov; Roderick T Bronson; Holly Goolsby; Simon C Watkins; Gregory A Cox; Robert H Brown
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-07-14
Journal Detail:
Title:  Human molecular genetics     Volume:  13     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-08-26     Completed Date:  2005-03-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1999-2010     Citation Subset:  IM    
Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
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MeSH Terms
Calpain / analysis,  metabolism
Caveolin 3
Caveolins / analysis,  metabolism
Disease Models, Animal
Dystrophin / analysis,  metabolism
Gene Expression
Gene Targeting
Membrane Proteins / analysis,  deficiency*,  genetics*
Mice, Mutant Strains
Muscle Proteins / analysis,  metabolism
Muscle, Skeletal / immunology,  metabolism,  ultrastructure
Muscular Dystrophies / etiology*,  metabolism,  pathology*
Mutation / genetics
RNA, Messenger / analysis,  metabolism
Sarcolemma / immunology,  metabolism,  pathology*
Reg. No./Substance:
0/Cav3 protein, mouse; 0/Caveolin 3; 0/Caveolins; 0/Dysf protein, mouse; 0/Dystrophin; 0/Membrane Proteins; 0/Muscle Proteins; 0/RNA, Messenger; EC 3.4.22.-/Calpain; EC 3.4.22.-/Capn3 protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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