Functional analysis of<i>RYR1</i>variants linked to malignant hyperthermia

Stephens, J. G.; Schiemann, Anja; Roesl, Cornelia; Miller, Dorota; Massey, Sean; Pollock, Neil; Bulger, Terasa; Stowell, Kathryn M.

doi:10.1080/23328940.2016.1153360

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…Variable myopathic phenotypes as well as malignant hyperthermia occur secondary to a variety of autosomal dominant missense mutations in heterozygous individuals. These are predominantly gain of function mutations in a heterozygous state that result in increased calcium efflux and a decrease in cellular calcium stores . Compound heterozygous and homozygous variants in RYR1 have been previously reported in cases that resulted in hydrops .…”

Section: Discussionmentioning

confidence: 99%

The utility of exome sequencing for fetal pleural effusions

et al. 2020

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Objective: We sought to evaluate the performance of exome sequencing (ES) in determining an underlying genetic etiology for cases of fetal pleural effusions. Study design: We examined a prospective cohort series of fetal pleural effusions visualized sonographically between 1 April 2016 and 31 August 2017. Fetal pleural effusions attributed to twin sharing, anemia, or structural anomalies were excluded, as were all cases with a genetic diagnosis established by karyotype or chromosomal microarray analysis. The remaining cases with pleural effusions of unclear etiology were offered ES. ES was performed by clinical sequencing and/or sequencing under the Baylor-Hopkins Center for Mendelian Genomics' (BHCMG) research platform. All cases were evaluated for novel genes or phenotypic expansion of disease-causing genes. Results: ES was performed on six probands affected by pleural effusions. A pathogenic variant was identified in one case (16.7%). Four additional cases had variants of uncertain significance (VUS) in candidate genes of pathological interest. Neither clinical nor candidate genes were evident in the final case. Conclusion: ES should be considered in the evaluation of prenatally detected idiopathic pleural effusions when other diagnostic workup for a genetic etiology has failed.

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Section: Discussionmentioning

confidence: 99%

The utility of exome sequencing for fetal pleural effusions

et al. 2020

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“…(15) Aberrant RyR-mediated Ca 2+ release has been associated with several diseases like malignant hyperthermia, (16) heart failure (17) and neurodegenerative diseases such as Huntington's disease (HD) (18) and Alzheimer's disease (AD). (19) These neurodegenerative diseases are characterized by the occurrence of protein aggregates (amyloid β in AD and mutant huntingtin in HD), which interfere with normal neuronal functioning.…”

Section: -Gated Intracellularmentioning

confidence: 99%

Basal ryanodine receptor activity suppresses autophagic flux

Vervliet

Pintelon

Welkenhuyzen

et al. 2017

Biochemical Pharmacology

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The inositol 1,4,5-trisphosphate receptors (IPRs) and intracellular Ca signaling are critically involved in regulating different steps of autophagy, a lysosomal degradation pathway. The ryanodine receptors (RyR), intracellular Ca-release channels mainly expressed in excitable cell types including muscle and neurons, have however not yet been extensively studied in relation to autophagy. Yet, aberrant expression and excessive activity of RyRs in these tissues has been implicated in the onset of several diseases including Alzheimer's disease, where impaired autophagy regulation contributes to the pathology. In this study, we determined whether pharmacological RyR inhibition could modulate autophagic flux in ectopic RyR-expressing models, like HEK293 cells and in cell types that endogenously express RyRs, like C2C12 myoblasts and primary hippocampal neurons. Importantly, RyR3 overexpression in HEK293 cells impaired the autophagic flux. Conversely, in all cell models tested, pharmacological inhibition of endogenous or ectopically expressed RyRs, using dantrolene or ryanodine, augmented autophagic flux by increasing lysosomal turn-over (number of autophagosomes and autolysosomes measured as mCherry-LC3 punctae/cell increased from 70.37±7.81 in control HEK RyR3 cells to 111.18±7.72 and 98.14±7.31 after dantrolene and ryanodine treatments, respectively). Moreover, in differentiated C2C12 cells, transmission electron microscopy demonstrated that dantrolene treatment decreased the number of early autophagic vacuoles from 5.9±2.97 to 1.8±1.03 per cellular cross section. The modulation of the autophagic flux could be linked to the functional inhibition of RyR channels as both RyR inhibitors efficiently diminished the number of cells showing spontaneous RyR3 activity in the HEK293 cell model (from 41.14%±2.12 in control cells to 18.70%±2.25 and 9.74%±2.67 after dantrolene and ryanodine treatments, respectively). In conclusion, basal RyR-mediated Ca-release events suppress autophagic flux at the level of the lysosomes.

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“…In recent years, functional studies have shed light on the mechanistic consequence of specific RYR1 variants, although these constitute < 10% of almost 700 known RYR1 variants [28, 40]. Variants associated with RYR1 -RD have been identified throughout the RYR1 coding and intronic regions and can lead to chronic SR Ca 2+ leak, decreased RyR1 protein levels, and RyR1 hyper- or hypo-sensitivity to agonists such as 4-chloro- m -cresol and caffeine [71, 72, 83, 95]. …”

Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9033-2) contains supplementary material, which is available to authorized users.

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Functional analysis ofRYR1variants linked to malignant hyperthermia

Cited by 16 publications

References 41 publications

The utility of exome sequencing for fetal pleural effusions

The utility of exome sequencing for fetal pleural effusions

Basal ryanodine receptor activity suppresses autophagic flux

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

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