Duchenne and Becker muscular dystrophy, Dr R. Roberts

Dr Roberts wishes to investigate which, if any, proteins interact with the “rod” region of the dystrophin protein (the protein that is missing in Duchenne muscular dystrophy).

Duchenne and Becker muscular dystrophy (DMD, BMD) represent the more and less severe forms of the same disease process, respectively and are both caused by mutations in the dystrophin protein. Dystrophin is very large and different parts of the protein are thought to have different functions. It consists of a long rod region with functional ends that bind to the cellular skeleton and to the cell membrane (see illustration for a simplified diagram). It is thought that the mutations causing BMD affect the central rod part of the protein so that a shorter, less functional version of the dystrophin protein is produced. In DMD, however, the mutations actually prevent the dystrophin protein from being produced or functioning at all.

Different forms of dystrophin are present in different tissues. The various forms are made by producing proteins of differing lengths that include different parts of the whole dystrophin protein. This allows tissues to have dystrophin proteins that perform slightly different functions. Dr Roberts is specifically interested in the rod region of the protein and in finding out if parts of the rod have specific functions that are utilised in different tissues.

It is possible that rather than merely being a structural beam, some parts of the rod have specific jobs and bind to other proteins in the cell. This may be a structural role that helps to stabilise the cell or it may be a signalling function that tells the cell when it needs to carry out particular functions. Shorter forms of the dystrophin protein are normally produced by tissues other than muscle such as the eye, brain and nerves. Dr Roberts believes that these special shorter forms of dystrophin have new functional ends that also bind to specific proteins.

The aim of this project, therefore, is to identify proteins which interact with parts of the rod and with the ends of the short dystrophin forms. This will help to improve our understanding of the function of dystrophin and also the consequences of having mutations in different parts of the dystrophin gene. This may help to explain the variation in severity of BMD, and why both BMD and DMD affect tissues other than muscle. It may also be useful in the design of gene therapy reagents.