Dysferlin and defective membrane repair in muscular dystrophy


We are studying a form of muscular dystrophy caused by deficiency of the protein dysferlin. Dysferlin patients have a primary defect in skeletal muscle membrane repair, and are unable to effectively repair small tears in their surface membranes that occur as part of normal activity. Defective muscle membrane repair is a new pathway implicated in the muscular dystrophies. Our research goal is to determine how dysferlin functions in its role as mediator of skeletal muscle membrane repair, to study the effect of dysferlin mutations we identify in our patients, and to identify proteins that interact with dysferlin and impact membrane repair pathways, as these proteins represent novel disease candidates for human muscular dystrophy.


Dr Sandra Cooper

Research Location

Westmead - Childrens Hospital at Westmead Clinical School

Program Type



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. 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. Our group is studying the molecular functions of dysferlin, in particular, how dysferlin senses calcium and responds to the injury.  We are using our access to patient tissue, cell lines and mutations to study the consequence of real-life patient mutations that only involve a single amino-acid change.  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. We have derived a large panel of dysferlin expression constructs which lack one or more of its calcium-binding C2 domains, or have targeted mutation of key residues which renders them calcium-insensitive.  In this way, we hope to determine which of the seven C2 domains play essential roles in the calcium-activated regulation of membrane resealing.  

Additional Information

Techniques used in this project will be broad and varied.

  1. Molecular Biology - to create new dysferlin expression constructs.
  2. Tissue Culture - to culture patient-derived muscle cell lines.
  3. Transfections – So we can induce expression of our mutant dysferlin constructs in cultured muscle cell lines.
  4. Western blot – so we can quantify the total levels of expressed protein in these cell lines.
  5. Immunohistochemistry – so we can specifically examine the levels and dynamics of cell surface dysferlin.
  6. Microscopy – Confocal microscopy and live cell imaging of our transfected cell lines. 
Our research team studies a form of inherited muscular dystrophy that is caused by deficient membrane repair, shedding light on the molecular steps of cell survival following membrane injury, and relevant to muscular dystrophy and heart attack. To help us decode how muscle and heart cells perform emergency membrane repair, please contact Dr Sandra Cooper (sandrac3@chw.edu.au, 02 9845 1456).

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Muscular dystrophy, neuromuscular disease, neurogenetics, inherited muscle disease, muscle, membrane repair, protein trafficking, tissue culture, Cell biology, Genetic disorders, Movement disorders, Genes in biology & medicine, Movement.

Opportunity ID

The opportunity ID for this research opportunity is: 148