title: Dysferlin overexpression in skeletal muscle produces a progressive myopathy.
abstract: OBJECTIVE
  The dose-response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy.
  
  
  METHODS
  We have generated 3 lines of transgenic mice, expressing low, mid, and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits.
  
  
  RESULTS
  Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca(2+)-regulated, dysferlin-binding proteins and endoplasmic reticulum stress chaperone proteins were observed in muscle lysates from transgenic mice as compared with controls.
  
  
  CONCLUSIONS
  Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this.
authors.affiliation: Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Kimberly
authors.initials: K
authors.lastname: Newton
authors.forename: Gomathi
authors.initials: G
authors.lastname: Krishnan
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Boyle
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Krivickas
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000073939:Dysferlin; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007738:Kyphosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007794:Lameness, Animal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins