CHARACTERISATION AND FUNCTIONAL ANALYSIS OF PROTEINS INVOLVED IN NEUROMUSCULAR DISEASES AND HEREDITARY CARDIOMYOPATHY

This research is a continuation of our work which led to the discovery and characterization of several muscle proteins: telethonin, ZASP, FATZ and the Ankrd2. A common feature of these four proteins is that they are located in the Z-disc, the complex molecular structure where actin filaments are anchored. The Z-disc also plays a central role in sensing muscle stress and reacting to it, by signalling to the nucleus to activate compensatory pathways. .In consideration of the Z-disc complexity, we should expect that genetic alteration of these genes could lead to genetic diseases. In fact, in collaboration with clinical groups, we established a link between the telethonin gene and a rare form of limb girdle muscular dystrophy, LGMD2G, and between the ZASP gene and a hereditary cardiomyopathy. .As a result of research both by us and other groups, the importance of these proteins in muscle function has become apparent. Recent studies allowed us to establish an intricate network of interactions for these four proteins. For example, telethonin can bind several proteins such as FATZ, Ankrd2, titin, myostatin, minK and MLP, but in most cases we do not know whether these interactions are mutual or competitive or whether post-translational modifications affect the binding specificity. .This research on the functional characterisation of Z-disc proteins has important implications for muscle physiology and hence the understanding of the aberrations leading to disease. Once the underlying mechanisms leading to the malfunctioning of muscle will be uncovered, various prospects of correcting or compensating for these defects will open, including gene therapy and hopefully in future pharmaceutical treatment to block or restore certain protein functions.