MUTATIONS IN THE RYANODINE RECEPTOR TYPE 1 GENE: ALTERATIONS OF CALCIUM HOMEOSTASIS AND NEUROMUSCULAR DISEASE

Central core disease (CCD) is a relatively mild, slowly progressive genetic myopathy characterised by muscle weakness and hypotonia; affected individuals show delayed motor development and their quality of life can be seriously jeopardised by the weakness of the skeletal muscle. Malignant hyperthermia (MH) is a potentially fatal neuromuscular disorder which occurs in genetically predisposed individuals when they are exposed to volatile anaesthetics and depolarising muscle relaxants such as suxamethonium. Both CCD and MH are linked to point mutations in the gene encoding the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor) which is localised on human chromosome 19. The ryanodine receptor is a key protein involved in the regulation of intracellular calcium concentration of muscle cells; the latter process plays a crucial role in muscle contraction. To date there are no effective therapies for the treatment of muscle weakness in CCD patients. The aim of this project is to evaluate the effect of salbutamol on the regulation of intracellular calcium concentration in muscle cells from CCD patients. The comprehension of the action of salbutamol on the regulation intracellular calcium in CCD muscle cells is of paramount importance to develop clinical trial with salbutamol for treatment of muscle weakness in CCD patients.