RyR1

RYR1 encodes ryanodine receptor type 1, a large intracellular calcium release channel predominantly expressed in skeletal muscle. The channel forms a homotetramer in the membrane of the sarcoplasmic reticulum and serves as the principal conduit for Ca2+ release during excitation-contraction coupling, triggering muscle contraction in response to depolarization of the muscle fiber.

The receptor is regulated by luminal Ca2+, calmodulin, FKBP12, calsequestrin, triadin and junctin, and is modulated by phosphorylation through PKA and CaMKII. In skeletal muscle, the interaction with the voltage-sensing DHPR (dihydropyridine receptor) links membrane depolarization to channel opening, enabling rapid Ca2+ release.

Genetics: RYR1 is located on chromosome 19q13.2. The gene encodes a very large protein (~5,000 amino acids) expressed mainly in skeletal muscle, with lesser expression in other tissues. Variants in RYR1 are associated with several inherited muscle disorders; many are inherited in an autosomal dominant fashion, though recessive forms exist.

Clinical significance: Pathogenic variants in RYR1 are a major cause of malignant hyperthermia susceptibility (MHS), a pharmacogenetic disorder where exposure to volatile anesthetics or depolarizing muscle relaxants triggers a hypermetabolic crisis. RYR1 mutations also cause central core disease and other congenital myopathies; phenotypes range from asymptomatic to severe weakness with core lesions on biopsy.

Diagnosis and treatment: Genetic testing identifies pathogenic RYR1 variants; in MH testing, the caffeine-halothane contracture test or genetic testing is used. Acute MH episodes require immediate dantrolene administration; long-term management includes avoidance of triggering agents and careful perioperative planning.