Limb-girdle muscular dystrophies (LGMDs) have highly overlapping phenotype and are associated with a number of causative genes. Clinical diagnosis of the disease sub-type is often difficult and molecular diagnosis is expensive given the genetic heterogeneity. Therefore, patients do not receive complete diagnosis.
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Although it proposed that dysferlin plays a key role in rapid calcium-mediated membrane resealing, very little is known regarding how it performs this role. The seven putative C2 domains within dysferlin suggest a high degree of modulation by intracellular calcium, likely mediating interactions central to its role in membrane repair. We are studying the cellular biology of dysferlin in cultured muscle cells, and have developed two membrane repair assays to study the functional role of dysferlin in membrane repair.
Genetically-defective dysferlin causes LGMD2B muscular dystrophy and mutated otoferlin causes DFNB9 deafness. Both proteins normally function by forming complexes with other proteins that either repair muscle (dysferlin) or promote hearing through sound-signal transmission (otoferlin). We are investigating the molecular role of dysferlin in muscle, guided by known ferlin interactions in inner ear hair cells, in an examination of the generalized molecular properties of dysferlin across tissues.
AAV gene therapy approaches for the treatment of dysferlinopathy have demonstrated efficacy in animal models using dual vectors or fragmented preparations capable of mediating oversized gene transduction. These approaches, while effective and interesting from a basic genetic standpoint, suffer from decreased transduction efficiencies. In particular, our work has demonstrated a concentration dependent effect: there is a larger transduction deficit for a multiple vector approach when the vector genomes are diluted (i.e.
Our data from earlier studies funded by the Jain Foundation suggest that intense loading of dysferlin-deficient murine skeletal muscle during exercise, does not cause acute muscle damage, but rather, causes extensive damage and inflammation that accrues over several days after loading. Our current Jain Foundation funded project is aimed at developing exercise programs that have the potential to reduce post-exercise muscle damage and inflammation in dysferlin-deficient skeletal muscle. We anticipate that our studies will provide useful information regarding exercise to patients with dysfer
We express and purify recombinant dysferlin proteins and are using an assortment of biochemical, biophysical, and microscopy assays to better understand how dysferlin regulates membrane structure and membrane fusion. The aims of this project are to 1) investigate the therapeutic potential of candidate small molecules by assessing their ability to restore function to recombinant dysferlin proteins harboring disease-causing mutations, and 2) investigate how alternative splicing of the dysferlin transcript affects the structure and lipid-binding activities of the resultant protein.