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Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

ABSTRACT: BACKGROUND:Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, functional studies must demonstrate a correlation with the pathophysiology of malignant hyperthermia or central core disease. OBJECTIVE:We assessed the pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis. The variants were identified in families affected by either malignant hyperthermia or central core disease. METHODS:Four variants were introduced separately into human cDNA encoding the skeletal muscle ryanodine receptor. Following transient expression in HEK-293T cells, functional studies were carried out using calcium release assays in response to an agonist. Two previously characterized variants and wild-type skeletal muscle ryanodine receptor were used as controls. RESULTS:The p.Met4640Ile variant associated with central core disease showed no difference in calcium release compared to wild-type. The p.Val4849Ile variant associated with malignant hyperthermia was more sensitive to agonist than wild-type but did not reach statistical significance and two variants (p.Phe4857Ser and p.Asp4918Asn) associated with central core disease were completely inactive. CONCLUSIONS:The p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia, while the p.Phe4857Ser and p.Asp4918Asn variants should be classified as pathogenic for central core disease.

SUBMITTER: Parker R

PROVIDER: S-EPMC5467713 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

Parker Remai R Schiemann Anja H AH Langton Elaine E Bulger Terasa T Pollock Neil N Bjorksten Andrew A Gillies Robyn R Hutchinson David D Roxburgh Richard R Stowell Kathryn M KM

Journal of neuromuscular diseases 20170101 2

<h4>Background</h4>Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, fu ...[more]

PMID: 28527222

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Project description:BackgroundWe investigated the potential safety of remimazolam and propofol in malignant hyperthermia- (HM-) susceptible patients using ryanodine receptor 1- (RYR1-) expressing human embryonic kidney- (HEK-) 293 cells.MethodsWe compared the enhanced responsiveness of HEK-293 cells expressing wild-type RYR1 with that of mutant RYR1 to caffeine following perfusion with remimazolam or propofol. Furthermore, we investigated whether RYR1 enhanced the responsiveness of cells to remimazolam or propofol and compared the median effective concentration (EC50; i.e., the concentration required to reach half-maximal activation) using an unpaired two-tailed t-test while a P < 0.05 was considered significant.ResultsRemimazolam and propofol did not promote the caffeine-induced increase in intracellular Ca2+ levels in HEK-293 cells expressing mutant RYR1 even with exposure to approximately 100-fold the clinically used concentration. In wild-type RYR1, EC50 values of remimazolam following refusion vs. nonperfusion were 2.86?mM vs. 2.75?mM (P = 0.76) while for propofol perfusion vs. nonperfusion, they were 2.76?mM vs. 2.75?mM, respectively (P = 0.83). In mutant RYR1, EC50 values of remimazolam refusion vs. nonperfusion were 1.58?mM vs. 1.71?mM, respectively (P = 0.63) while for propofol perfusion vs. nonperfusion, they were 1.65?mM vs. 1.71?mM, respectively (P = 0.73). Remimazolam and propofol increased intracellular Ca2+ levels in a concentration-dependent manner, but the effect was not enhanced by RYR1. EC50 values of remimazolam with non-RYR1 vs. wild-type RYR1 were 1.00?mM vs. 0.92?mM, respectively (P = 0.91) while those of propofol were 1.09?mM vs. 1.05?mM, respectively (P = 0.84).ConclusionsThe increase in intracellular Ca2+ concentration caused by remimazolam or propofol was not considered an RYR1-mediated reaction. We conclude that remimazolam and propofol can be safely used as an anesthetic in MH-susceptible patients with RYR1-mutation without causing MH and may be safely substituted for an MH-triggering anesthetic when RYR1-mediated MH occurs.

Dataset Information

Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

Publications

Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

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