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Zullo A, et al. [110] 2019
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R1335C, S2345R, S3098I, F4924_V4925ins
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RYR1 sequence variants in myopathies: Expression and functional studies in two families
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Ca2+ release in response to the RyR1 agonist 4-chloro-m-cresol and to thapsigargin showed that S2345R causes depletion of S/ER Ca2+ stores and that the compound heterozygosity for variant S3098I and the 30-nucleotide insertion increases RyR1-dependent Ca2+ release without affecting ER Ca2+ stores
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Johannsen S, et al. [111] 2016
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R4737W
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Functional characterization of the RYR1 mutation pArg4737Trp associated with susceptibility to malignant hyperthermia
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Intracellular resting calcium was slightly but significantly elevated in mutation positive cells. Calcium release following stimulation with 4-chloro-m-cresol was significantly increased in B lymphocytes carrying the R4737W mutation compared to mutation negative controls
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Schiemann AH, et al. [112] 2014
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R2355W, V2354M
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Functional characterization of 2 known ryanodine receptor mutations causing malignant hyperthermia
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We propose that R2355W is confirmed as being an MH-causative mutation and suggest that V2354M is a RYR1 mutation likely to cause MH
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Lyfenko AD, et al. [66] 2007
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R4214_F4216del
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Two central core disease (CCD) deletions in the C-terminal region of RYR1 alter muscle excitation-contraction (EC) coupling by distinct mechanisms
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ΔRQF RYR1 deletion did not significantly affect the sensitivity of lymphoblastoid cells to activation by 4-CmC. However, Ca21 release activated by a maximal concentration of 4-CmC (1 mM) was significantly reduced in ΔRQF-carrying cells
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Schiemann AH, et al. 2013
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R1583C, V2102L
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Sequence capture and massively parallel sequencing to detect mutations associated with malignant hyperthermia
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The amount of Ca2+ released after stimulation with 4-chloro-m-cresol from B lymphocytes of the MH-susceptible patients in the family was significantly greater compared with that of Ca2+ released from cells of an MH-negative family member
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Attali R, et al. [113] 2013
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Y3016C
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Variable myopathic presentation in a single family with novel skeletal RYR1 mutation
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Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca2+ stores
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Vukcevic M, et al. [114] 2010
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R1679H, K1393R, E1058K, H382N, R2508G
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Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease
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All B lymphoblastoid cell lines carrying RYR1 candidate mutations showed significantly increased resting cytoplasmic Ca2+ levels as well as a shift to lower concentrations of 4-CmC inducing calcium release compared with controls
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Grievink H, et al. [115] 2010
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H4833Y
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Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia
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Allele-specific differences in RYR1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes
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Zozato F, et al. [72] 2003
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F4863_D4869delinsT
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Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor
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Cells have depleted thapsigargin-sensitive intracellular Ca2+ stores, exhibit release of Ca2+ from intracellular stores in the absence of the addition of a pharmacological activator of the RYR1; and the unelicited Ca2+ transient from the thapsigargin-sensitive stores could be blocked by dantrolene, a specific inhibitor of the skeletal muscle RYR
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Zullo A, et al. [116] 2009
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R530H, R2163P, N2342S, E2371G, R2454H, C4664R
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Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes
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Increased acidification rate of lymphoblastoid cells in response to 4-CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N-terminal and in the central region of the protein (R530H, R2163P, N2342S, E2371G and R2454H) displayed higher activity compared with controls. Cell lines harboring RYR1(C4664R) were significantly less activated by 4-CmC
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Levano S, et al. [117] 2009
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D554Y, R2336H, E2404K, D2730G
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Increasing the number of diagnostic mutations in malignant hyperthermia
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All RYR1 mutations significantly increased resting calcium concentration and significantly affect either 4-CmC or caffeine dose-response curve to pharmacological activation Only one mutation (D2730G) showed a significant reduction in EC50 of both caffeine and 4-CmC
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Anderson AA, et al. [118] 2008
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H4833Y
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Identification and biochemical characterization of a novel ryanodine receptor gene mutation associated with malignant hyperthermia
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B lymphocytes from patients with this mutation were approximately twofold more sensitive than MH-negative cells to activation with 4-CmC. The amount of Ca2+ released from B lymphocytes of MH-susceptible patients was significantly greater than that released from cells of family members without this mutation
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Ducreux D, et al. [119] 2006
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P3527S, V4849I, R999H
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Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes
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P3527S in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-CmC and caffeine but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on the size of the intracellular Ca2+ stores, or the amount of Ca2+ released after ryanodine receptor activation P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration
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Tilgen N, et al. [120] 2001
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R4861H, I4898T, G4899A
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Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: Association with central core disease and alteration of calcium homeostasis
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Cell showed release of Ca2+ from intracellular stores in the absence of any pharmacological activators of RYR, significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals, and a normal sensitivity of the calcium release to the RYR inhibitor dantrolene
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Girard T, et al. [121] 2001
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V2168M
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B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators
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EBV immortalized cells harboring the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-CmC and their peripheral blood leukocytes produce more interleukin-1beta after treatment with the RYR activators caffeine and 4-CmC, compared with cells from healthy controls
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Hoppe K, et al. [122] 2016
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R530H, C4664R, R2163P
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Hypermetabolism in B–lymphocytes from malignant hyperthermia susceptible individuals
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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.
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