Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21817 (RyR1)
 1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central core disease, one of the most common congenital myopathies in humans, has been linked to mutations in the RYR1 gene encoding the Ca(2+) release channel of the sarcoplasmic reticulum (RyR1). Functional analyses showed that disease-associated RYR1 mutations led to impairment of skeletal muscle Ca(2+) homeostasis; however, thorough understanding of the molecular mechanisms underlying central core disease and other RyR1-related conditions is still lacking. We screened by sequencing the complete RYR1 transcripts in ten unrelated patients with central core disease and identified five novel, p.M4640R, p.L4647P, p.F4808L, p.D4918N and p.F4941C, and four recurrent mutations. Four of the novel mutations involved amino acid residues that were positioned within putative transmembrane segments of the RyR1. The pathogenic character of the identified mutations was demonstrated by bioinformatic analyses and by the in vitro functional studies in HEK293 cells and RYR1-null (dyspedic) myotubes. Characterization of Ca(2+) channel properties of RyR1s carrying one recurrent and two novel mutations upholds the view that diminished intracellular Ca(2+) release caused by impaired Ca(2+) channel gating and/or Ca(2+) permeability is an important component of central core disease etiology. This study expands the list of functionally characterized disease-associated RyR1 mutations, increasing the value of genetic diagnosis for RyR1-related disorders.
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PMID:Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease. 2318 35

Central core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level.
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PMID:Exon skipping as a therapeutic strategy applied to an RYR1 mutation with pseudo-exon inclusion causing a severe core myopathy. 2380 38

Central core disease (CCD) is a genetically heterogeneous congenital myopathy, and ryanodine receptor 1 (RYR1, gene ID6261) is the only pathogenicity gene until now. Data on mutation characteristics of RYR1 in the Chinese CCD population are scarce. This study searched for mutations in the C-terminal-encoding domain of RYR1 in six Chinese patients with CCD, and identified five missense mutations (N4807F, R4861H, R4893P, G4897D, and I4898T). Among them, N4807F, G4897D were novel while R4861H, R4893P, and I4898T were previously reported. All missense mutations were highly conserved across the species of human, mouse, rabbit, fish, and pig. This study found that mutations could be identified in about 85% CCD patients, even if only the C-terminal-encoding region of RYR1 was screened. Many mutations clustered in exons 100-102.
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PMID:Novel RYR1 missense mutations in six Chinese patients with central core disease. 2456 Oct 95

Myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene are amongst the most common non-dystrophic neuromuscular disorders and have been associated with both dominant and recessive inheritance. Several cases with apparently de novo dominant inheritance have been reported. Here we report two siblings with features of Central Core Disease (CCD) born to unaffected parents. Genetic testing revealed a heterozygous dominant RYR1 c.14582G>A (p. Arg4861His) mutation previously identified in other CCD pedigrees. The variant was absent in blood from the asymptomatic mother but detected at low but variable levels in blood- and saliva-derived DNA from the unaffected father, suggesting that this mutation has arisen as a paternal post-zygotic de novo event. These findings suggest that parental mosaicism should be considered in RYR1-related myopathies, and may provide one possible explanation for the marked intergenerational variability seen in some RYR1 pedigrees.
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PMID:Parental mosaicism in RYR1-related Central Core Disease. 2957 27

Central Core Disease (CCD) is a congenital myopathy characterized by presence of amorphous central areas (or cores) lacking glycolytic/oxidative enzymes and mitochondria in skeletal muscle fibers. Most CCD families are linked to mutations in ryanodine receptor type-1 (RYR1), the gene encoding for the sarcoplasmic reticulum (SR) Ca2+ release channel of skeletal muscle. As no treatments are available for CCD, currently management of patients is essentially based on a physiotherapic approaches. Functional electrical stimulation (FES) is a technique used to deliver low energy electrical impulses to artificially stimulate selected skeletal muscle groups. Here we tested the efficacy of FES in counteracting muscle loss and improve function in the lower extremities of a 55-year-old female patient which was diagnosed with CCD at the age of 44. Genetic screening of the RyR1 gene identified a missense mutation (c.7354C>T) in exon 46 resulting in an amino acid substitution (p.R2452W) and a duplication (c.12853_12864dup12) in exon 91. The patient was treated with FES for 26 months and subjected before, during, and after training to a series of functional and structural assessments: measurement of maximum isometric force of leg extensor muscles, magnetic resonance imaging, a complete set of functional tests to assess mobility in activities of daily living, and analysis of muscle biopsies by histology and electron microscopy. All results point to an improvement in muscle structure and function induced by FES suggesting that this approach could be considered as an additional supportive measure to maintain/improve muscle function (and possibly reduce muscle loss) in CCD patients.
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PMID:Functional Electrical Stimulation: A Possible Strategy to Improve Muscle Function in Central Core Disease? 3119 25

Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.
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PMID:In vivo RyR1 reduction in muscle triggers a core-like myopathy. 3317 65


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