Back Row (left to right) Leigh Waddell; Dr Rachel Peat; Dr Janine Smith; Dr Sandra Cooper; Frances Evesson.
Front Row (left to right) Dr Harriet Lo; Dr Alison Compton.

Many forms of muscular dystrophy are associated with a structural fragility of the muscle membrane, whereby membrane damage exceeds the ability of muscle to repair itself, resulting in the progressive degeneration of muscle fibres.  We are studying a new form of muscular dystrophy, caused by mutations in the gene dysferlin.  Rather than having a structural role, dysferlin has recently been shown to play a role in repairing the small sites of membrane damage caused through normal physical activity.  In dysferlin patients, the structure of the membrane is normal, but membrane repair is impaired.

Membrane repair is mediated by the aggregation and fusion of vesicles beneath the site of injury, forming a “patch” that can seal ruptures in the cell membrane. Membrane repair is a calcium-dependent process, and, muscle fibres deficient in dysferlin exhibit much slower and more inefficient membrane repair, similar to that observed in wild-type muscle fibres in the absence of calcium.  Thus, it is proposed that dysferlin plays a role as a calcium-sensor at sites of membrane disruption, and somehow orchestrates vesicle aggregation and patch repair of damaged membranes.

Muscle is a specialised tissue and particularly prone to damage.  Although we know that dysferlin is essential for efficient muscle membrane repair, we don’t know exactly how, or with whom, it performs this role.  There are many patients with muscular dystrophy in whom the genetic basis for their disorder is unknown.  It is likely that some of these patients have defects in other proteins that interact with dysferlin and/or are involved in membrane repair pathways.

Dysferlin is a large transmembrane protein, with multiple predicted calcium-binding domains, and a handful of known proteins with which it interacts.  The dysferlin and membrane repair team has several goals. 1) To define which region(s) of dysferlin mediate interaction with known binding partners, and, to identify novel binding partners. 2) To determine how dysferlin is transported from the site where it is made, to its final destination at the muscle membrane, and which domains regulate this targeting. 3) To study the effect of mutations identified in patients with dysferlinopathy. Many patients have only a single amino-acid changed within the large dysferlin protein (2080 amino acids).  These changes necessarily represent key amino-acids essential for folding, trafficking or function.  Study of these mutations can be a powerful tool to gain a greater understanding of the normal biology of dysferlin, and how this is disrupted in patients with dysferlin disease.