Author/Year | RYR1 variant(s) | Title | Conclusions |
---|---|---|---|
HEK-293 | |||
Chirasani VR, et al. [34] 2019 | Q3970K, Q3970E | A central core disease mutation in the Ca2+ binding site of skeletal muscle ryanodine receptor impairs single channel regulation | RyR1-Q3970K is likely a CCD-associated loss-of-function channel that conducts Ca2+ |
Xu L, et al. [35] 2018 | G4934D, G4934K, G4941D, G4941K, G4941M, D4938N, D4945N | G4941K substitution in the pore-lining S6 helix of the skeletal muscle ryanodine receptor increases RyR1 sensitivity to cytosolic and luminal Ca2+ | Luminal Ca2+ accesses Ca2+ activation sites as they pass through the pore rather than traveling to openings that lie outside the pore |
Xu L, et al. [36] 2018 | E3893Q, E3893V, E3967Q, E3967V, T5001A | Ca2+ − mediated activation of the skeletal-muscle ryanodine receptor ion channel | Removal of negative charges in a RyR1 Ca2+ binding site impairs activation of RyR1 by physiological concentrations of Ca2+, and suggests loss of binding to or reduced Ca2+ affinity of the site |
Xu L, et al. [37] 2008 | G4898E, G4898R, ΔV4926, ΔI4927, R110W, L486V | Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies | Homozygous RyR1 mutations associated with core myopathies abolish or greatly reduce sarcoplasmic reticulum Ca2+ release during excitation-contraction coupling |
Schiemann AH, et al. [38] 2018 | D2431Y | A genetic mystery in malignant hyperthermia ‘solved’? | The D2431Y variant is pathogenic for MH and should be added to the European Malignant Hyperthermia Group (EMHG) list of diagnostic mutations |
Murayama T, et al. [39] 2018 | G342R, R2435H, L4824P | Efficient High-Throughput Screening by Endoplasmic Reticulum Ca2+ Measurement to Identify Inhibitors of Ryanodine Receptor Ca2+ − Release Channels | In the current high throughput screening of 1535 compounds, we identified four RyR1 inhibitors |
Kondo T, et al. [40] 2018 | T84M | Genetic and functional analysis of the RYR1 mutation pThr84Met revealed a susceptibility to malignant hyperthermia | Functional analysis of T84M demonstrated higher responsivity to caffeine and 4CmC |
Parker R, et al. [41] 2017 | M4640I, V4849I, F4857S, D4918N | Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia | The V4849I variant should be considered a risk factor for malignant hyperthermia, while the F4857S and D4918N variants should be classified as pathogenic for CCD |
Merritt A, et al. [42] 2017 | R2336H, R2355W, E3104K, G3990V, V4849I, D3986E | Assessing the pathogenicity of RYR1 variants in malignant hyperthermia | Functional analyses in HEK293 cells provided evidence to support the use of R2336H, R2355W, E3104K, pG3990V and V4849I for diagnostic purposes but not D3986E |
Chen W, et al. [43] 2017 | R164C, Y523S, R2136H, R2435H, Y4796C | Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease | All mutations reduced the threshold for SOICR |
Stephens J et al. [44] 2016 | ΔE2348, T214M | Functional analysis of RYR1 variants linked to malignant hyperthermia | ΔE2348 could be added to the list of diagnostic mutations for susceptibility to malignant hyperthermia T214M, does not appear to significantly alter sensitivity to agonist in the same system |
Murayama T, et al. [45] 2016 | R2163C, R2163H, V2168M, T2206M, A2350T, G2375A, G2434R, R2435H, R2454C, R2454H, R2458C, R2458H, R2508C, R2508H | Genotype–Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel | In live-cell Ca2+ imaging, the mutant channels exhibited an enhanced sensitivity to caffeine, a reduced endoplasmic reticulum Ca2+ content, and an increased resting cytoplasmic Ca2+ level |
Gomez AC, et al. [46] 2016 | F4732D, G4733E, R4736W, R4736Q, T4825I, H4832Y, T4082M, S4113L, N4120Y | Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation | Nine RyR1 mutants associated with skeletal muscle diseases were differently regulated by Ca2+ and Mg2+ |
Murayama T, et al. [47] 2015 | C36R, R164C, R164L, G249R, G342R, R402C, R402H, Y523C, Y523S, R615C, R615L | Divergent Activity Profiles of Type 1 Ryanodine Receptor Channels Carrying Malignant Hyperthermia and Central Core Disease Mutations in the Amino-Terminal Region | The mutations increased the gain and the sensitivity to activating Ca2+ in a site-specific manner. Gain was consistently higher in both MH and MH/CCD mutations |
Miyoshi H, et al. [48] 2015 | R2508H, R2508G, R2508S, R2508K | Several Ryanodine Receptor Type 1 Gene Mutations of pArg2508 Are Potential Sources of Malignant Hyperthermia | Cells transfected with each of the 4 mutants, R2508H, R2508G, R2508S, or R2508K, were more sensitive to caffeine and 4CmC than wild-type cells |
Mei Y, et al. [49] 2015 | G4934A, G4934V, G4941V, G4941A, G4941I | Channel Gating Dependence on Pore Lining Helix Glycine Residues in Skeletal Muscle Ryanodine Receptor | Both glycines are important for RyR1 channel function by providing flexibility and minimizing amino acid clashes |
Shirvanyants D, et al. [50] 2014 | M4887G, M4887A, M4887V, V4891A, I4897Y | Pore dynamics and conductance of RyR1 transmembrane domain | Loss of these interactions in the case of polar substitution I4897T results in destabilization of the selectivity filter, a possible cause of the CCD-specific reduced Ca2+ conductance |
Roesl C, et al. [51] 2014 | R2452W | Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility | R2452W results in a hypersensitive ryanodine receptor 1 and is likely to be causative of MH |
Miyoshi H, et al. [52] 2014 | R2508C, R2508H, R2508K, R2508S | Two different variants of p.2508 in Japanese malignant hyperthermia patients causing hypersensitivity of ryanodine receptor 1 | All alterations in the p.2508 portion of RyR1 play important roles in the pathogenesis of MH |
Sato K, et al. [53] 2013 | R44C, R163C, R401C, R533C, R533H, H4833Y | Skeletal muscle ryanodine receptor mutations associated with malignant hyperthermia showed enhanced intensity and sensitivity to triggering drugs when expressed in human embryonic kidney cells | These six mutations cause functional abnormality of the calcium channel, leading to higher sensitivity to a specific agonist |
Kraeva N, et al. [54] 2013 | M4640R, L4647P, F4808L, D4918N, F4941C | Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease | Homotetrameric RyR1 mutants harbouring L4646P, F4807P, D4917N and R4892Q mutations abolished caffeine-induced Ca2+ release |
Merritt A, et al. [55] 2012 | D1056H | Functional analysis of the pD1056H RYR1 variant associated with malignant hyperthermia and exertional heat stroke | Cells expressing D1056H exhibited a trend for greater calcium release and increased sensitivity than wild-type at low doses of caffeine |
Murayama T, et al. [56] 2011 | T4825A, T4825I, I4826A, L4827A, S4828A, S4829A | Role of amino-terminal half of the S4-S5 linker in type 1 ryanodine receptor (RyR1) channel gating | Four mutants had reduced CICR activity without changing Ca2+ sensitivity, whereas the L4827A mutant formed a constitutive active channel T4825I, a disease-associated mutation for malignant hyperthermia, exhibited enhanced CICR activity |
Haraki T, et al. [57] 2011 | A4894T, A4894P, A4894S, A4894G | Mutated p.4894 RyR1 function related to malignant hyperthermia and congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) | The hypersensitive A4894T-RyR1 is associated with MH and the poorly functional A4894P-RyR1 with CNMDU1 |
Zhou H, et al. [58] 2010 | R2939K | Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene | The R2435K mutation did not affect two characteristic functional properties of RyR1, as both Ca2+ dependence and activation by caffeine were not altered |
Sato K, et al. [59] 2010 | R163C, G248R, T4826I, H4833Y, I4898T, G4899R | Functional studies of RYR1 mutations in the skeletal muscle ryanodine receptor using human RYR1 complementary DNA | MH mutations showed a higher response, whereas CCD mutants (I4898T and G4899R) did not respond to 4-Cm C |
Merritt A, et al. [60] 2010 | G3990V | Functional analysis of the pGly3990Val RYR1 variant using a human cDNA clone in HEK293 cells | A statistically significant increase in Ca2+ release was observed in G3990V mutants at each caffeine concentration that elicited a response |
Migita T, et al. [61] 2009 | R2508C | Functional analysis of ryanodine receptor type 1 pR2508C mutation in exon 47 | The transfected RYR1 mutant was more sensitive to caffeine and 4CmC than wildtype RYR1 |
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+ |
Ghassemi F, et al. [63] 2009 | R2435L | A recessive ryanodine receptor 1 mutation in a CCD patient increases channel activity | R2435L does not affect resting Ca2+, or sensitivity of RyR1 to pharmacological activators Instead it reduces the release of Ca2+ from intracellular stores induced by pharmacological activators as well as by KCl via the voltage sensing dihydropyridine receptor |
Jiang D, et al. [64] 2008 | R615C | Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia | R615C confers MH susceptibility by reducing the threshold for luminal Ca2+ activation and SOICR |
Rossi D, et al. [65] 2007 | R4836fsX4838 | A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres | Subtle changes in Ca2+ release of human heteromeric RyR1/RyR1R4837fsX4839 channels, probably due to the reduced stability/assembly of these channels, may predispose individuals to MHS |
Lyfenko AD, et al. [66] 2007 | R4214_F4216del, V4927_I4928del | Two central core disease (CCD) deletions in the C-terminal region of RYR1 alter muscle excitation-contraction (EC) coupling by distinct mechanisms | Single channel data indicate that the ΔRQF mutation increases Ca2+ responsiveness without altering K+ conductance and ion selectivity for Ca2+ compared to K+. In contrast, the ΔVI deletion abolished Ca2+ responsiveness, Ca2+ permeation, and significantly reduced K+ conductance demonstrating that the ΔVI mutation introduced major alterations to the channel pore |
Zhou H, et al. [67] 2006 | S71Y, R110W, L486V, A1578T, S2060C, N2283H | Characterization of recessive RYR1 mutations in core myopathies | Recombinant channels with N2283H substitution showed an increased activity, whereas recombinant channels with S71Y + N2283H substitution lost activity upon isolation |
Xu L, et al. [68] 2006 | D4938N, D4945N, D4953N, E4942Q, E4948Q, E4952Q, E4955Q | Two rings of negative charges in the cytosolic vestibule of type-1 ryanodine receptor modulate ion fluxes | D4938N and D4945N exhibited an attenuated block by neomycin to a greater extent from the cytosolic than lumenal side. By comparison, charge neutralization of lumenal loop residues (D4899Q, E4900N) eliminated the block from the lumenal but not the cytosolic side |
Wang Y, et al. [69] 2005 | D4899Q, E4900N | Probing the role of negatively charged amino acid residues in ion permeation of skeletal muscle ryanodine receptor | the negatively charged carboxyl oxygens of D4899 and E4900 side chains are major determinants of RyR ion conductance and selectivity |
Brini M, et al. 2005 [70] | R615C, Y523S, I4898T | Ca2+ signaling in HEK-293 and skeletal muscle cells expressing recombinant ryanodine receptors harboring malignant hyperthermia and central core disease mutations | I4898T RyR1 channels produced cytosolic Ca2+ values which were similar to those observed for WT RyR1 channels R615C augmented the amplitude of the cytosolic and mitochondrial Ca2+ transients following cell stimulation By contrast, the mitochondrial Ca2+ transients were reduced in cells expressing Y523S |
Du GG, et al. [71] 2004 | R4892W, I4897T, G4898E | Central core disease mutations R4892W, I4897T and G4898E in the ryanodine receptor isoform 1 reduce the Ca2+ sensitivity and amplitude of Ca2+-dependent Ca2+ release | Ca2+ sensitivity is one of the serious defects in these three excitation-contraction uncoupling CCD mutations |
Zozato F, et al. [72] 2003 | F4863_D4869delinsT | Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor | Channels carrying the deletion were less stable than the wild-type channels and disappeared rapidly when recorded at membrane potentials greater than ±20 mV |
Stange M, et al. [73] 2003 | S2843D, S2843A | Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants | Results did not support the view that phosphorylation of a single site (RyR1-Ser-2843 and RyR2-Ser-2809) substantially changes RyR1 and RyR2 channel function |
Loke JC, et al. [74] 2003 | R328W | Detection of a novel ryanodine receptor subtype 1 mutation (R328W) in a malignant hyperthermia family by sequencing of a leukocyte transcript | The mutant channel has increased sensitivity to both caffeine and halothane |
Yamaguchi N, et al. [75] 2001 | V3619A, W3620A, L3624D, Δ4274–4535 | Identification of apocalmodulin and Ca2+ − calmodulin regulatory domain in skeletal muscle Ca2+ release channel, ryanodine receptor | Two single amino acid substitutions distinctly change the regulation of the skeletal muscle Ca2+ release channel by CaM; one of which (L3624D) results in a loss of activation by apoCaM and an inhibition by CaCaM, whereas the other (W3620A) specifically abolishes CaCaM inhibition RyR1Δ4274–4535, showed an ∼10-fold increased sensitivity to activating Ca2+ |
Sun J, et al. [76] 2001 | C3635A | Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO | C3635A resulted in the loss of CaM-dependent NO modulation of channel activity and reduced S-nitrosylation by NO to background levels but did not affect NO-independent channel modulation by CaM or the redox sensitivity of the channel to O(2) and glutathione |
Gaburjakova M, et al. [77] 2001 | V2461H, V2461E, V2461G, V2461I | FKBP12 binding modulates ryanodine receptor channel gating | Val2461 is a critical residue required for FKBP12 binding to RyR1 FKBP12 has a functional role in the RyR1 channel complex |
Du GG, et al. [78] 2001 | G2370A, G2372A, G2373A, G2375A, Y3937A, S3938A, G3939A, K3940A | Mutations to Gly2370, Gly2373 or Gly2375 in malignant hyperthermia domain 2 decrease caffeine and cresol sensitivity of the rabbit skeletal-muscle Ca2+ − release channel (ryanodine receptor isoform 1) | Amino acids 2370–2375 lie within a sequence (amino acids 2163–2458) in which 8 RyR1 mutations associated with MH have been shown to be hypersensitive to caffeine and 4-chloro-m-cresol activation By contrast, G2370A, G2373A and G2375A are hyposensitive to caffeine and 4-chloro-m-cresol Amino acids 2163–2458 form a regulatory domain (MH regulatory domain 2) that regulates caffeine and 4-chloro-m-cresol sensitivity of RyR1 |
Monnier N, et al. [79] 2000 | Y4796C | An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor | Expression of the mutant RYR1 cDNA produced channels with increased caffeine sensitivity and a significantly reduced maximal level of Ca2+ release Single-cell Ca2+ analysis showed that the resting cytoplasmic level was increased by 60% in cells expressing the mutant channel |
Gao L, et al. [80] 2000 | I4897A, I4897L, I4897V, D4917A, D4899A, D4899R, R4913E, G4894A, D4899N | Evidence for a role of the lumenal M3-M4 loop in skeletal muscle Ca2+ release channel (ryanodine receptor) activity and conductance | Amino acid residues in the lumenal loop region between the two most C-terminal membrane segments constitute a part of the ion-conducting pore of RyR1 |
Tong J, et al. [81] 1999 | C36R, G249R, G342R, R553W, R615R, R615C, R2163C, G2435R, R2458C, R2458H, R164C, I404M, Y523S, R2163H, R2436H | Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels | MH/CCD mutants were more sensitive to caffeine than WT RyR1, indicating that caffeine hypersensitivity observed with a variety of MH/CCD mutant RyR1 proteins is not dependent on extracellular Ca2+ concentration |
Lynch PJ, et al. [82] 1999 | I4898T | A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease | Single-cell analysis of co-transfected cells showed a significantly increased resting cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level These data are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ concentration required for channel activation |
Tong J, et al. [83] 1997 | R164C, G249R, G342R, I404M, Y523S, R615C, G2435R, R2436H, C36R, R553W, R615L, R2163C, R2163H, R2458C, R2458H | Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease | Abnormal sensitivity in the Ca2+ photometry assay provides supporting evidence for a causal role in MH for each of 15 single amino acid mutations in the ryanodine receptor |