Résumé :
|
A growing number of congenital neuromuscular disorders are linked to mutations in RYR1, the gene encoding the RyR1 Ca2+ release channel. Indeed more than 200 distinct mutations in RYR1 have been identified to date in patients with the subclinical myopathy Malignant Hyperthermia (MH), King Denborough syndrome, the congenital core myopathy central core disease, some forms of multiminicore disease, centronuclear myopathy and congenital fiber type disproportion. Over the past decades our research has focused on understanding the mechanisms whereby mutations in the same gene (the RYR1) can be associated with such variable and at times opposing phenotypes. We as well as others have established that one class of RYR1 mutations causes the channels to become hypersensitive to activation by electrical and pharmacological stimuli (MH). A second class of mutations (CCD) result in leaky channels leading to depletion of Ca2+ from intracellular stores. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the sarcoplasmic reticulum. The fourth class of mutations cause a decrease of RyR1 protein expression on SR membranes. Such alterations of the functional properties of the RyR1 are also associated with alterations of downstream Ca2+ - dependent signalling pathways which may participate in the pathological process. Understanding how mutations directly and indirectly affect the properties of the Ca2+ release channel may help develop novel therapeutic strategies aimed at improving muscle function in this group of patients suffering from congenital myopathies.
|