Central core disease, multi-minicore disease and malignant hyperthermia have been 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 (RYR1). The ryanodine receptor is a key protein involved in the regulation of the intracellular calcium concentration in muscle cells and plays a crucial role in muscle contraction, releasing the calcium from the sarcoplasmic reticulum after plasma membrane depolarization. Central core disease and multi-minicore disease are neuromuscular disorders characterized by hypotonia during infancy, muscle weakness and delayed motor development. They differ in their clinical phenotypes and modes of inheritance. Central core disease is a relatively mild, slowly progressive autosomal dominant myopathy, characterised histologically by the presence of centrally located cores running the length of the muscle fibres. Multi-minicore disease is a more severe, rare, autosomal recessive congenital myopathy characterized histologically by the presence of multiple cores in only a small number of sarcomeres. The subclinical myopathy malignant hyperthermia is a potentially fatal pharmacogenetic disorder occurring in predisposed individuals when they are exposed to volatile anaesthetics and depolarising muscle relaxants such as suxamethonium. The study of the functional properties of ryanodine receptor channels carrying mutations linked to neuromuscular disorders is important from a diagnostic point of view but also to understand the basic pathophysiological mechanism leading to these different diseases. In fact understanding the mechanisms leading to dysregulation of calcium homeostasis is of fundamental importance if one is to develop a pharmacological treatment to improve the quality of life of affected patients. To date there are no effective therapies for the treatment of muscle weakness in central core disease and multi-minicore disease patients, while for malignant hyperthermia presymtomatic diagnosis is fundamental. There are three isoforms of the ryanodine receptor which are expressed in different tissues; type 1 is preferentially expressed in skeletal muscles but recent data revealed that it is also expressed in B-lymphocytes and immature dendritic cells.

The aims of this project are: (i) investigate the effect of novel mutations in cells endogenously expressing the RYR1 (in EBV immortalized lymphoblastoid cells, myoD transduced fibroblasts and cultured myotubes); (ii) determine the role of the ryanodine receptor in cells of the immune systems; in fact B-cells as well as dendritic cells act as antigen presenting cells during the immune response and thus play an important role in adaptive and innate immunity. We have previously demonstrated that immortalized B lymphoblastoid cells express a functional ryanodine receptor 1. In this project we will extend these studies and investigate the role of the ryanodine receptor in human dendritic cells and investigate whether the immune system bears any role in the pathophysiology of malignant hyperthermia, central core disease and multi minicore disease. In addition we plan to investigate if the presence of MH-linked mutations may have a beneficial role on the immune system. Such a finding would substantiate our hypothesis that RYR1 mutations may have been conserved during evolution because they offer a selective beneficial advantage to carriers, by enhancing some immunological functions