Résumé :
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Communication n° 704. Dysferlin is a sarcolemmal and vesicular protein whose deficiency causes limb-girdle muscular dystrophy type 2B, Miyoshi myopathy and anterior distal muscular dystrophy. Dysferlin is a member of the ferlin protein family, C2 domain-containing proteins encoded by a multiple gene family which share homology with the C. elegans, sperm vesicle fusion protein FER-1. Four human ferlin genes have been reported dysferlin, otoferlin, myoferlin and FER1L4. Of these, dysferlin and otoferlin have been implicated in genetic disease. Recent data emerging for dysferlin highlights that that this putative membrane fusion protein is a component of the sarcolemmal repair machinery. In wild type muscle cells dysferlin is mobilised to the injury site following membrane injury. Dysferlin deficient muscle fibres are defective in resealing membrane disruptions. We are working to identify novel sarcolemmal repair proteins, which may function as compensatory proteins in dysferlin deficiency. Starting with an in silico approach we have identified novel human ferlins. Comparative sequence analyses and homology modelling of their C2 domains has defined two functional subclasses of ferlin proteins, dysferlin-like and otoferlin-like. The dysferlin subgroup contains myoferlin and the novel FER1L5. All of the genes of the dysferlin subgroup ferlins are upregulated during myoblast fusion. Like dysferlin, FER1L5 shows predominant muscle expression. We have shown that the membrane trafficking of dysferlin and myoferlin is highly similar in intact muscle cells. Following membrane injury of muscle cells myoferlin is also mobilised to the injury site like dysferlin. Our co-localisation studies suggest that myoferlin is not present in known membrane repair vesicles. We have hypothesised that myoferlin and FER1L5 have a role in membrane repair. We are currently generating myoferlin and FER1L5 deficient cells for membrane repair assays.
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