Skip to main content

Table 7 Other RYR1 preclinical model systems

From: Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990–2019

Author/Year Species/RYR1 variant(s) Title Conclusions
Gupta VA, et al. [263] 2013 Zebrafish (Danio rerio)/ ryr1b mi340 Developing therapies for congenital myopathies by high throughput chemical screening in ryanodine receptor 1 mutant zebrafish A secondary screen using individual chemicals from positive pools is in progress to identify the best combination of chemical/s that improve muscle function and survival of ryr1b mutant fish
Dowling JJ, et al. [28] 2012 Zebrafish (Danio rerio)/ ryr1b mi340 Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy Oxidative stress is an important pathophysiological mechanism in RYR1-related myopathies and that N-acetylcysteine is a successful treatment modality ex vivo and in a vertebrate disease model
Dowling JJ, et al. [264] 2011 Zebrafish (Danio rerio)/ ryr1b mi340 Increased oxidative stress and successful antioxidant treatment in a vertebrate model of RYR1 related myopathy Increased oxidative stress is an important aspect of the pathogenesis of RYR1-related myopathies, and antioxidant treatment is a viable potential treatment strategy for patients
Dowling JJ, et al. [265] 2010 Zebrafish (Danio rerio)/ ryr1b mi340 Oxidative stress and RYR1-related myopathies Loss of RYR1 function in the zebrafish results in increased levels of basal oxidative stress and increased susceptibility to pro-oxidants. RYR1 deficient zebrafish treated with anti-oxidants had significant improvements in motor function
Dowling JJ, et al. [266] 2009 Zebrafish (Danio rerio)/ ryr1b mi340 Oxidative stress and antioxidant therapy in a zebrafish model of multi minicore myopathy Loss of RYR1 function results in increased oxidative stress in a vertebrate model of RYR1 related myopathy. Antioxidant therapy can improve motor function
Hirata H, et al. [267] 2007 Zebrafish (Danio rerio)/ ryr1b mi340 Zebrafish relatively relaxed mutants have a ryanodine receptor defect, show slow swimming and provide a model of multi-minicore disease Zebrafish relatively relaxed mutants may be useful for understanding the development and physiology of MmD
Oyamada H, et al. [268] 2002 Hamster (CHO cells)/ P4667S, L4837V, R615C Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients L4838V was responsible for increased sensitivity of RyR1 to caffeine P4667S had very little effect on the caffeine-induced Ca2+ increase
Treves S, et al. [84] 1994 Monkey (COS-7 cells)/ R615C Alteration of intracellular Ca2+ transients in COS-7 cells transfected with the cDNA encoding skeletal-muscle ryanodine receptor carrying a mutation associated with malignant hyperthermia. Presence of the Arg-to-Cys point mutation in the recombinant RYR expressed in COS-7 transfected cells causes abnormal cytosolic Ca2+ transients in response to 4-chloro-m-cresol, an agent capable of eliciting in vitro contracture of MH-susceptible muscles.
Altafaj X, et al. [85] 2005 Monkey (COS-7 cells)/ RyR1ΔF7 (3241-3661Del) Maurocalcine and domain A of the II-III loop of the dihydropyridine receptor Cav 1.1 subunit share common binding sites on the skeletal ryanodine receptor. RyR1 carrying a deletion of fragment 7 shows a loss of interaction with both peptide A and maurocalcine. This deletion abolishes the maurocalcine induced stimulation of [3H] ryanodine binding onto microsomes of transfected COS-7 cells without affecting the caffeine and ATP responses.
Vega AV, et al. [269] 2011 C2C12 (mouse)/ Y524S, I4897T Calcitonin gene-related peptide restores disrupted excitation-contraction coupling in myotubes expressing central core disease mutations in RyR1 Changes in excitation–contraction coupling induced by the expression of RyR1 channels bearing CCD mutations Y523S or I4897T can be reversed by calcitonin gene related peptide
Lefebvre R, et al. [270] 2011 Swiss OF1 (mouse)/Y523S, R615C, R2163H, I4897T Defects in Ca2+ release associated with local expression of pathological ryanodine receptors in mouse muscle fibres The Y523S, R615C and R2163H RyR1 mutants produce a similar over-sensitive activation of the calcium flux whereas I4897T RyR1 mutants are responsible for a depressed Ca2+ flux. The alterations appear to result from inherent modifications of RyR1 channel function and not from indirect changes in the muscle fibre homeostasis
Douris V, et al. [271] 2017 Drosophila model/G4946V, G4946E, I4790M Investigation of the contribution of RyR target-site mutations in diamide resistance by CRISPR/Cas9 genome modification in Drosophila Mutations confer subtle differences on the relative binding affinities of the three diamides at an overlapping binding site on the RyR protein
Gao S, et al. [272] 2013 Drosophila model/ Q3878X, Y4452X, R4305C, E4340K, P2773L Drosophila ryanodine receptors mediate general anesthesia by halothane Neurally expressed dRyr mediates a substantial proportion of the anesthetic effects of halothane in vivo, is potently activated by halothane in vitro, and activates an inhibitory conductance
Sullivan KM, et al. [273] 2000 Drosophila model/Ryr16ins The ryanodine receptor is essential for larval development in Drosophila melanogaster The ryanodine receptor is required for proper muscle function and may be essential for excitation-contraction coupling in larval body wall muscles Results do not support a role for Ryr in normal light responses
Wilberger MS, et al. [274] 2015 Equine model/ C7360G Prevalence of exertional rhabdomyolysis in endurance horses in the Pacific Northwestern United States Exertional rhabdomyolysis in this group was not associated with known genetic mutations tied to type 1 PSSM and MH
Nieto JE, et al. [275] 2009 Equine model/ C7360G A rapid detection method for the ryanodine receptor 1 (C7360G) mutation in Quarter Horses Genotyping by melting curve analysis with hybridization probes is a rapid and accurate detection method for the RyR1 C7360G mutation that works on both cDNA and gDNA
Aleman M, et al. [276] 2009 Equine model/ C7360G Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in Quarter Horses MH is a potentially fatal disease of Quarter Horses that could be triggered by halogenated anesthetics and other nonanesthetic factors that may include exercise, stress, breeding, illnesses, and concurrent myopathies
Aleman M, et al. [277] 2004 Equine model/ R2454G Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia A missense mutation in RyR1 is associated with MH in the horse, providing a screening test for susceptible individuals. Ryanodine-binding analysis suggests that long-lasting changes in RyR1 conformation persists in vitro after the triggering event
Roberts MC, et al. [278] 2001 Canine model/V547A Autosomal dominant canine malignant hyperthermia is caused by a mutation in the gene encoding the skeletal muscle calcium release channel (RYR1) Autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel The MHS trait in this pedigree of mixed-breed dogs is in perfect co-segregation with the RYR1 V547A mutation
Baines KN, et al. [279] 2017 Caenorhabditis elegans/G341R, R2163H, R2454H, R2458H, R4861H, A4940T, R163C, K3452Q Aging Effects of Caenorhabditis elegans Ryanodine Receptor Variants Corresponding to Human Myopathic Mutations Single amino acid modifications in C. elegans also conferred a reduction in lifespan and an accelerated decline in muscle integrity with age, supporting the significance of ryanodine receptor function for human aging
Baines KN, et al. [280] 2014 Caenorhabditis elegans (unc-68)/ G341R, R2163H, R2454H, R2458H, R4861H, A4940T, R163C, K3452Q Caenorhabditis elegans as a model organism for RYR1 variants and muscle ageing The ryanodine receptor in Caenorhabditis elegans is UNC-68, which has 40% amino acid identity to the human protein
Hamada T, et al. [281] 2002 Caenorhabditis elegans/ kh30, e540, × 14, r1161 Molecular dissection, tissue localization and Ca2+ binding of the ryanodine receptor of Caenorhabditis elegans We propose a model for the functional domains of CeRyR, which agrees well with the model of mammalian skeletal RyR, which is based on proteolysis and cross-linking analysis
Maryon EB, et al. [282] 1998 Caenorhabditis elegans (unc-68)/ r1161, r1162, r1221, e540 Muscle-specific functions of ryanodine receptor channels in Caenorhabditis elegans Unlike vertebrates, which have at least three ryanodine receptor genes, C elegans has a single gene encoded by the unc-68 locus. Unc-68 is expressed in most muscle cells, and the phenotypic defects exhibited by unc-68 null mutants result from the loss of unc-68 function in pharyngeal and body-wall muscle cells
Sakube Y, et al. [283] 1997 Caenorhabditis elegans (unc-68)/ e540, unc-68 null An abnormal ketamine response in mutants defective in the ryanodine receptor gene ryr-1 (unc-68) of Caenorhabditis elegans S1444N substitution is at a putative protein kinase C phosphorylation site in ryr-1 unc-68(e540) contains a splice acceptor mutation that creates a premature stop codon in the ryr-1 gene
Maryon EB, et al. [284] 1996 Caenorhabditis elegans (unc-68)/ rl l51, rl152, rl158, rl160, rl161, r1162, r1167, r1207, r1208, rl209, r1210, r1211, r1212, rDfl, rDf2 unc-68 encodes a ryanodine receptor involved in regulating C elegans body-wall muscle contraction The role of RyRs in C elegans body-wall muscle is to enhance contraction by amplifying a depolarization-coupled Ca2+ transient
Airey JA, et al. [285] 1993 Crooked Neck Dwarf (cn/cn) alpha RyR-null Failure to make normal alpha ryanodine receptor is an early event associated with the crooked neck dwarf (cn) mutation in chicken Failure to make normal alpha RyR receptor appears to be an event closely associated with the cn mutation and one which may be largely responsible for development of the cn/cn phenotype in embryonic skeletal muscle
Airey JA, et al. [286] 1993 Crooked Neck Dwarf (cn/cn) alpha RyR-null Crooked neck dwarf (cn) mutant chicken skeletal muscle cells in low density primary cultures fail to express normal alpha ryanodine receptor and exhibit a partial mutant phenotype The mutant phenotype observed in ovo is partially expressed under low density culture conditions, and neither beta RyR protein nor its function appear to be capable of preventing the associated changes
Ivanenko A, et al. [287] 1995 Crooked Neck Dwarf (cn/cn) alpha RyR-null Embryonic chicken skeletal muscle cells fail to develop normal excitation-contraction coupling in the absence of the alpha ryanodine receptor. Implications for a two-ryanodine receptor system In the absence of alpha RyR there is a failure to develop Ca2+ − independent Ca2+ release and contractions and to sustain Ca2+ − dependent release. Moreover, contributions by the alpha RyR cannot be duplicated by the beta RyR alone
Oppenheim RW, et al. [288] 1997 Crooked Neck Dwarf (cn/cn) alpha RyR-null Neuromuscular development in the avian paralytic mutant crooked neck dwarf (cn/cn): further evidence for the role of neuromuscular activity in motoneuron survival It seems likely that the peripheral excitation of muscle by motoneurons during normal development is a major factor in regulating retrograde muscle-derived (or muscle-associated) signals that control motoneuron differentiation and survival