Author/Year | Species/RYR1 variant(s) | Title | Conclusions |
---|---|---|---|
Suman M, et al. [123] 2018 | N4575T, I1571V, L3136Rfs, R163C, I4898T, Q4837RfsX3 | Inositol trisphosphate receptor-mediated Ca2+ signaling stimulates mitochondrial function and gene expression in core myopathy patients | Remodeling of skeletal muscle Ca2+ signaling following loss of functional RyR1 mediates bioenergetic adaptation |
Choi RH, et al. [124] 2017 | R1976C | Dantrolene requires Mg2+ to arrest malignant hyperthermia | Accumulation of the metabolite Mg2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode |
Hoppe K, et al. [122] 2016 | G2434R, R614C | Hypermetabolism in B-lymphocytes from malignant hyperthermia susceptible individuals | Native B–lymphocytes from MHS individuals are more sensitive to 4–CmC than those from MHN, reflecting a greater Ca2+ turnover. The acidification response, however, was less pronounced than in muscle cells, presumably reflecting the lower expression of RyR1 in B–lymphocytes |
Kaufmann A, et al. [125] 2012 | A612P, R2458H, R3348C | Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families | Results suggest that these variants are new causative MH variants |
Treves S, et al. [126] 2010 | V2168M, R2336H, R614C, D2730G, R44C, R789L | Enhanced excitation-coupled Ca2+ entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease | Excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CCD |
Kobayashi M, et al. [127] 2011 | L4838V, R2508C | Analysis of human cultured myotubes responses mediated by ryanodine receptor 1 | Among samples from CICR-accelerated patients, there was an increased sensitivity to RYR1 activators compared to non-accelerated patients. The EC50 values for these different compounds correlated with results of CICR testing. Using this approach may be a sensitive and specific method of identifying patients predispose to MH |
Migita T, et al. [62] 2009 | R2508C, A4894T | Do Ca2+ channel blockers improve malignant hyperthermia crisis? | The dantrolene-induced decline effect of Ca2+ of skeletal muscle was not disappeared in the presence of Ca2+ blockers. In MH crisis, we do not recommend to administer Ca2+ blockers because of its potent effect to increase Ca2+ |
R2508C, L4838V | Propofol-Induced Changes in Myoplasmic Calcium Concentrations in Cultured Human Skeletal Muscles from RYR1 Mutation Carriers | Increases in calcium concentrations in response to propofol dosage were limited to doses at least 100-fold greater than those used in clinical settings. These observations correlate well with clinical observations that propofol does not trigger malignant hyperthermia in susceptible humans | |
Zhou, et al. [130] 2006 | R109W, M402T, M2423K, R2939K, A4329D, T4709M | Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies | RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this unveils recessive mutations in patients with core myopathies |
Weigl LG, et al. [131] 2004 | G2434R | 4-Chloro-m-cresol cannot detect malignant hyperthermia equivocal cells in an alternative minimally invasive diagnostic test of malignant hyperthermia susceptibility | Cells of MHEH individuals showed low sensitivities against both caffeine and 4-CmC, comparable to those of the MHN group. Therefore, with myotubes, caffeine was able to discriminate between MHS and MHN cells, but both caffeine and 4-CmC failed to detect MHEH cells |
Wehner M, et al. [132] 2004 | A2350T, R2355W, G2375A | Functional characterization of malignant hyperthermia-associated RyR1 mutations in exon 44, using the human myotube model | Investigation of calcium homeostasis with the calcium sensitive probe Fura 2 showed a higher sensitivity to the ryanodine receptor agonists 4-chloro-m-cresol, caffeine and halothane for the myotubes derived from the mutation carriers as compared to those of the control group |
Ducreux S, et al. [133] 2004 | V2168M, I4898T, R4893W | Effect of ryanodine receptor mutations on interleukin-6 release and intracellular calcium homeostasis in human myotubes from malignant hyperthermia-susceptible individuals and patients affected by central core disease | Abnormal release of calcium via mutated RYR enhances the production of the inflammatory cytokine IL-6, which may in turn affect signaling pathways responsible for the trophic status of muscle fibers |
Wehner M, et al. [134] 2003 | I2182F, G2375A | Calcium release from sarcoplasmic reticulum is facilitated in human myotubes derived from carriers of the ryanodine receptor type 1 mutations Ile2182Phe and Gly2375Ala | In myotubes of individuals carrying the RyR1 Ile2182Phe or the RyR1 Gly2375Ala mutation, the EC(50) for caffeine and halothane was reduced; in the Ile2182Phe myotubes, the EC(50) for 4CmC was also reduced, all consistent with facilitated calcium release from the sarcoplasmic reticulum. From these data we conclude that both mutations are pathogenic for MH |
Wehner M, et al. [135] 2003 | I2453T | The Ile2453Thr mutation in the ryanodine receptor gene 1 is associated with facilitated calcium release from sarcoplasmic reticulum by 4-chloro-m-cresol in human myotubes | The reduction of EC(50) indicates a facilitated calcium release from sarcoplasmic reticulum in the myotubes of the index patient suggesting that the RYR1 Ile2453Thr mutation is pathogenic for the malignant hyperthermia susceptibility and CCD of the two affected individuals |
Wehner M, et al. [136] 2002 | T2206M | Increased sensitivity to 4-chloro-m-cresol and caffeine in primary myotubes from malignant hyperthermia susceptible individuals carrying the ryanodine receptor 1 Thr2206Met (C6617T) mutation | In myotubes the half-maximal activation concentration (EC(50)) for 4-chloro-m-cresol was reduced from 203 micro m (wild type) to 98 micro m (Thr2206Met), and for caffeine from 3.8 mm to 1.8 mm. From the reduction of EC(50) we conclude that the RyR1 Thr2206Met mutation is pathogenic for MH |
Sei Y, et al. [137] 2002 | C35R, R163C, G248R, G341R, I403M, R552W, R614C, R614L, R2163C, R2163H, V2168, V2214I, A2367T, D2431N, G2434R, R2435H, R2454C, R2454H, R2458C, R2458H, I4898T | Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes | The Ca2+ responses to caffeine or 4-chloro-m-cresol in B lymphocytes showed significant differences between MHS and MHN (or control) individuals. Although the molecular mechanisms of these alterations are currently undetermined, the results suggest that the enhanced Ca2+ responses are associated with mutations in the RYR1 gene in some MHS individuals |
Girard T, et al. [138] 2002 | R614C, G2434R, V2168M, R2458C | Phenotyping malignant hyperthermia susceptibility by measuring halothane-induced changes in myoplasmic calcium concentration in cultured human skeletal muscle cells | Measurements of Ca2+ in human skeletal muscle cells can be used to phenotype MH susceptibility; however, we did not observe a specific effect of any mutation in the RYR1 gene on the halothane-induced increase in Ca2+ |
Brinkmeier H, et al. [139] 1999 | G2435R | Malignant hyperthermia causing Gly2435Arg mutation of the ryanodine receptor facilitates ryanodine-induced calcium release in myotubes | The phenotype of MH can be characterized using cultured human muscle and a culture-based test for MH susceptibility may eventually be developed. |
Censier K, et al. [140] 1998 | R163C | Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors | Cultured human skeletal muscle cells derived from MH-susceptible individuals exhibit a half-maximal halothane concentration causing an increase in intracellular Ca2+ concentration which is twofold lower than that of cells derived from MH-negative individuals. The resting Ca2+ concentration of cultured skeletal muscle cells from MH-negative and MH-susceptible individuals is not significantly different |