MOLECULAR PATHOLOGY OF RYANODINE RECEPTOR MUTANTS LINKED TO CENTRAL CORE DISEASE AND MALIGNANT HYPERTHERMIA

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. Dysregulation of calcium signals due to mutated ryanodine receptor may account for the phenotype of patients with CCD and MH. This project is focused on the comprehension of the pathogenetic mechanism of ryanodinopathies, a crucial step to develop effective therapies for patients affected by CCD and related neuromuscular disorders.