Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B‐lymphocytes

@article{Zullo2009FunctionalCO,
  title={Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B‐lymphocytes},
  author={Alberto Zullo and Werner Klingler and Claudia De Sarno and Marina Ferrara and Giuliana Fortunato and Giuseppa Perrotta and Elvira Gravino and Rosella Di Noto and Frank Lehmann-Horn and Werner Melzer and Francesco Salvatore and Antonella Carsana},
  journal={Human Mutation},
  year={2009},
  volume={30}
}
Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi‐minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4‐chloro‐m‐cresol (4‐CmC) and the rate of extracellular… 
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Identification and Functional Analysis of RYR1 Variants in a Family with a Suspected Myopathy and Associated Malignant Hyperthermia.
TLDR
The p.Trp661* RYR1 variant should be considered as a risk factor for myopathies and the role of the p.Pro816Leu variant in MH remains unclear.
Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility.
SEQUENCE VARIANTS IN THE RYR1 GENE AND GENETIC DISEASES: MALIGNANT HYPERTHERMIA AND CONGENITAL MYOPATHIES
TLDR
This PhD thesis has been focused on the identification and functional characterization of sequence variants in the RYR1 gene, associated with Malignant hyperthermia (MH) and some congenital myopathies (CMs), and showed alterations in the functional activity of the RYP1 mutated channel.
Functional Studies of RYR1 Mutations in the Skeletal Muscle Ryanodine Receptor Using Human RYR1 Complementary DNA
TLDR
Functional assays validate recombinant human skeletal muscle ryanodine receptor for analysis of variants and add an additional mutation (H4833Y) to the repertoire of mutations that can be used for the genetic diagnosis of malignant hyperthermia.
Functional Studies of RYR 1 Mutations in the Skeletal Muscle Ryanodine Receptor Using Human RYR 1 Complementary DNA
TLDR
Functional assays validate recombinant human skeletal muscle ryanodine receptor for analysis of variants and add an additional mutation (H4833Y) to the repertoire of mutations that can be used for the genetic diagnosis of malignant hyperthermia.
Novel missense mutations and unexpected multiple changes of RYR 1 gene in 75 malignant hyperthermia families
TLDR
It is confirmed that MH is genetically heterogeneous and that a consistent number of cases are not due to RYP1 mutations, and the discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.
RYR1 Sequence Variants in Myopathies: Expression and Functional Studies in Two Families
TLDR
It is demonstrated that, in patient-specific lymphoblastoid cells, the c.4003C>T (p.R1335C) variant is not expressed and the in-frame 30-nucleotide insertion variant is expressed at a low level, and Ca2+ release in response to the RyR1 agonist 4-chloro-m-cresol and to thapsigargin showed that the c.
Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance
TLDR
Blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYP1 exons and additionally for known variants of CACNA1S to examine whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants.
Correlation of phenotype with genotype and protein structure in RYR1-related disorders
TLDR
Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders and are corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.
Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990–2019
TLDR
Findings from these studies have set the foundation for therapeutic development for MH and RYR1 -RM, a spectrum of rare neuromuscular disorders, which have been developed to better understand underlying pathomechanisms and test potential therapeutics.
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References

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Identification and Biochemical Characterization of a Novel Ryanodine Receptor Gene Mutation Associated with Malignant Hyperthermia
TLDR
DNA analysis to detect mutations which cosegregate with MH as well as biochemical assays on cultured lymphocytes obtained from blood can serve as useful diagnostic tools for MH susceptibility and genotype–phenotype correlations.
Mutations in RYR1 in malignant hyperthermia and central core disease
The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation–contraction coupling and skeletal muscle calcium homeostasis. Mapping to…
Characterization of recessive RYR1 mutations in core myopathies.
TLDR
The data suggest major differences in the ways RYR1 mutations may affect patients with core myopathies, by compromising RyR1 protein expression, stability and/or activity.
Identification of a novel mutation in the ryanodine receptor gene (RYR1) in a malignant hyperthermia Italian family
TLDR
The identification by two independent methods of a novel mutation associated with the MH-susceptible phenotype in the RYR1 gene: the 6488G->C transversion, resulting in the replacement of the Arg2163 with a proline residue is reported.
Effect of Ryanodine Receptor Mutations on Interleukin-6 Release and Intracellular Calcium Homeostasis in Human Myotubes from Malignant Hyperthermia-susceptible Individuals and Patients Affected by Central Core Disease*
TLDR
The results suggest that abnormal release of calcium via mutated RYR enhances the production of the inflammatory cytokine IL-6, which may in turn affect signaling pathways responsible for the trophic status of muscle fibers.
A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease.
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  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
Comparison with two other coexpressed mutant/normal channels suggests that the I4898T mutation produces one of the most abnormal RyR1 channels yet investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected central core disease individuals.
Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores
TLDR
All cases presenting with a quantitative defect of RYR1 expression in a panel of patients affected by recessive core myopathies were caused by the presence of one recessive null allele and that variability of the phenotype depended on the nature of the mutation present on the second allele.
Functional Defects in Six Ryanodine Receptor Isoform-1 (RyR1) Mutations Associated with Malignant Hyperthermia and Their Impact on Skeletal Excitation-Contraction Coupling*
TLDR
This study demonstrates for the first time that these 7 MH mutations are all both necessary and sufficient to induce MH-related phenotypes.
Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors.
TLDR
It is shown for the first time that cultured human skeletal muscle cells derived from MH-susceptible individuals exhibit a half-maximal halothane concentration causing an increase in intracellular Ca2+ concentration which is twofold lower than that of cells derivedfrom MH-negative individuals.
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