Mutations in the RYR1 gene are the most common cause of nondystrophic congenital myopathies. Mutations in RYR1 were initially identified in individuals susceptible to malignant hyperthermia, a pharmacogenetic disorder triggered by volatile anesthetics and succinylcholine. Shortly after, mutations in RYR1 were identified in patients with central core disease, which is the most frequent congenital myopathy, and in other muscle disorders, collectively referred to as RYR1-related myopathies. RYR1 mutations are also responsible of some acute pathological conditions triggered by heat- and exercise-induced stress, named exertional heat stroke and exertional-induced rhabdomyolysis, which, similarly to malignant hyperthermia, occur in otherwise healthy individuals with normal skeletal muscle functions. Hundreds of causative mutations linked to RYR1-related diseases have been identified. These mutations are clustered in three regions that are referred to as the N-terminal, central, and C-terminal hot spots. Recent developments in cryo-EM techniques have provided high-resolution reconstructions of the channel, allowing a much better definition of the structural domains within the large N-terminal cytoplasmic region and in the C-terminal domain containing six transmembrane helices and the pore region of the channel. RYR1 mutations may either activate or inhibit channel function or, in some cases, can reduce the expression levels of RYR1 protein. However, similar clinical phenotypes can result from mutations with opposing effects on RYR1 function, or little or no correlation can be found between the observed clinical phenotype and localization of mutations in the structural domains of the RYR1 channel, even though recent studies indicate that clinically severe cases are mostly recessive or due to mutations located in the bridging solenoid. Recent results on the identification of RYR1 mutations in patients with myopathies will be presented.
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