Intracellular accumulation and reduced sarcolemmal expression of dysferlinin limb-girdle muscular dystrophies

Dysferlin has recently been identified as a novel gene involved in limb-gir dle muscular dystrophy type 2B (LGMD2B) and its allelic disease, Miyoshi my opathy. The predicted structure of dysferlin suggests that it is a transmem brane protein possibly involved in membrane fusion. Thus, unlike previously identified structural proteins in muscular dystrophy, dysferlin is likely involved in a novel pathogenic mechanism for this disease. In this study, w e have analyzed the expression of dysferlin in skeletal. muscle of patients with disruptions in the dystrophin-glycoprotein complex and patients with a clinical diagnosis of LGMD2B or Miyoshi myopathy. We show expression of d ysferlin at the sarcolemma in normal muscle and reduced sarcolemmal express ion along with accumulation of intracellular staining in dystrophic muscle. Electron microscopy in Miyoshi myopathy biopsies suggests that the cytopla smic staining could be a result of the abundance of intracellular vesicles. Our results indicate that dysferlin expression is perturbed in LGMD and th at both mutations in the dysferlin gene and disruption of the dystrophin-gl ycoprotein complex can lead to the accumulation of dysferlin within the cyt oplasm.