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

Abstract

Background Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics. Methods We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019. Results Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported. Conclusions Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.

A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy

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Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

“…The two main pathophysiological mechanisms of RyR1 diseases are either alteration of calcium channel permeability or reduction in the amount of protein. A comprehensive review of the different preclinical models available for RYR1-related myopathies was recently published [ 143 ]. Models described below for compound heterozygous RYR1 mutations carry one frameshift mutation together with a missense mutation in the other allele, resulting in low levels of RyR1 proteins with mono-allelic expression of the missense mutation.…”

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility

“…For the purpose of assessing RYR1 transfection studies to weight PS3, results are dichotomized into pathogenic EC50 values that are significantly decreased as compared to WT versus benign EC50 values that are not significantly decreased. For RYR1 pathogenicity assessment, the whole of prior published work (Figure 1, Table S2) 22 allows us to consider transfection assays in HEK293 cells using photometry/imaging to measure calcium release a well defined functional test. However, recommendations for increased stringency in analyses of functional data have recently been suggested.…”