Dysferlin Mutants: Defects in Trafficking and Association with Proteins of the Transverse Tubule

Abstract

Dysferlinopathies are a class of muscular dystrophies caused by a loss of function or expression of dysferlin, a 237 kDa single-pass transmembrane protein expressed in many tissues, including skeletal muscle. Dysferlin has been implicated in sarcolemmal repair and in the regulation of calcium signaling following mechanical stress. Dysferlin binds to several proteins associated with the transverse tubules, including the dihydropyridine receptor (DHPR) and Caveolin 3, to stabilize the triad junction and perhaps to serve as a scaffold for repair machinery. Mutations disrupting these interactions may lead to disruption of Ca signaling after mechanical stress, which in turn leads to fiber loss, inflammation and muscle atrophy associated with muscular dystrophy. Mutations to dysferlin may also to lead to aberrant trafficking, causing accumulation in compartments other than the T-tubules, therefore removing or reducing dysferlin's function. We are studying several point mutations found in dysferlinopathy patients, as well as domain deletion mutants, to determine their effects on trafficking, association with other membrane proteins, and dimerization. Our results to date indicate that mutations or deletions that are thought to be pathogenic are at least partially associated with altered trafficking to the T-tubules and, for some, disruption of binding to Cav3, but not to changes in its ability to dimerize. Supported by the Jain Foundation and NIH RO1 AR064268.