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)

The skeletal muscle ryanodine receptor gene (RYR1; OMIM 180901) on chromosome 19q13.1 encodes the skeletal muscle calcium release channel. To date, more than 25 missense mutations have been identified in RYR1 and are associated with central core disease (CCD; OMIM 117000) and/or the malignant hyperthermia susceptibility phenotype (MHS1; OMIM 145600). The majority of RYR1 mutations are clustered in the N-terminal hydrophilic domain of the protein. Only four mutations have been identified so far in the highly conserved C-terminal region encoding the luminal/transmembrane domain of the protein which forms the ion pore. Three of these mutations have been found to segregate with pure or mixed forms of CCD. We have screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients, diagnosed clinically and/or histologically as having CCD. We have identified five missense mutations (four of them novel) in 13 index patients. The mutations cluster in exons 101 and 102 and replace amino acids which are conserved in all known vertebrate RYR genes. In order to study the functional effect of these mutations, we have immortalized B-lymphocytes from some of the patients and studied their [Ca(2+)](i) homeostasis. We show that lymphoblasts carrying the newly identified RYR1 mutations exhibit: (i) a release of calcium from intracellular stores in the absence of any pharmacological activators of RYR; (ii) significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and (iii) a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. Our data suggest the C-terminal domain of RYR1 as a hot spot for mutations leading to the CCD phenotype. If the functional alterations of mutated RYR channels observed in lymphoblastoid cells are also present in skeletal muscles this could explain the predominant symptom of CCD, i.e. chronic muscle weakness. Finally, the study of calcium homeostasis in lymphoblastoid cells naturally expressing RYR1 mutations offers a novel non-invasive approach to gain insights into the pathogenesis of MH and CCD.
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PMID:Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. 1174 31

Three CCD (central core disease) mutants, R4892W (Arg4892-->), I4897T and G4898E, in the pore region of the skeletal-muscle Ca2+-release channel RyR1 (ryanodine receptor 1) were characterized using a newly developed assay that monitored Ca2+ release in the presence of Ca2+ uptake in microsomes isolated from HEK-293 cells (human embryonic kidney 293 cells), co-expressing each of the three mutants together with SERCA1a (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 1a). Both Ca2+ sensitivity and peak amplitude of Ca2+ release were either absent from or sharply decreased in homotetrameric mutants. Co-expression of wild-type RyR1 with mutant RyR1 (heterotetrameric mutants) restored Ca2+ sensitivity partially, in the ratio 1:2, or fully, in the ratio 1:1. Peak amplitude was restored only partially in the ratio 1:2 or 1:1. Reduced amplitude was not correlated with maximum Ca2+ loading or the amount of expressed RyR1 protein. High-affinity [3H]ryanodine binding and caffeine-induced Ca2+ release were also absent from the three homotetrameric mutants. These results indicate that decreased Ca2+ sensitivity is one of the serious defects in these three excitation-contraction uncoupling CCD mutations. In CCD skeletal muscles, where a mixture of wild-type and mutant RyR1 is expressed, these defects are expected to decrease Ca2+-induced Ca2+ release, as well as orthograde Ca2+ release, in response to transverse tubular membrane depolarization.
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PMID:Central core disease mutations R4892W, I4897T and G4898E in the ryanodine receptor isoform 1 reduce the Ca2+ sensitivity and amplitude of Ca2+-dependent Ca2+ release. 1517 1

Dysregulation of calcium signals because of defects of the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), central core disease (CCD; MIM #11700), specific forms of multi-minicore disease (MmD; MIM # 255320) and centronuclear myopathy (CNM). Experimental data have shown that RYR1 mutations result mainly in four types of channel defects: one class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to depletion of Ca(2+) from SR stores. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR. The fourth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels expression on SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.
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PMID:Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm. 1831 59

Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients' muscle biopsies. We defined "dusty cores" the irregular areas of myofibrillar disorganisation characterised by a reddish-purple granular material deposition with uneven oxidative stain and devoid of ATPase activity, which represent the characteristic lesion in muscle biopsy in 54% of patients. We named Dusty Core Disease (DuCD) the corresponding entity of congenital myopathy. Dusty cores had peculiar histological and ultrastructural characteristics compared to the other core diseases. DuCD muscle biopsies also showed nuclear centralization and type1 fibre predominance. Dusty cores were not observed in other core myopathies and centronuclear myopathies. The other morphological groups in our cohort of patients were: Central Core (CCD: 21%), Core-Rod (C&R:15%) and Type1 predominance "plus" (T1P+:10%). DuCD group was associated to an earlier disease onset, a more severe clinical phenotype and a lowest level of RyR1 expression in muscle, compared to the other groups. Variants located in the bridge solenoid and the pore domains were more frequent in DuCD patients. In conclusion, DuCD is the most frequent histopathological presentation of RYR1-recessive myopathies. Dusty cores represent the unifying morphological lesion among the DuCD pathology spectrum and are the morphological hallmark for the recessive form of disease.
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PMID:'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. 3061 13

This article presents an experimental investigation of the flame characteristics of the gasoline pool fire. A series of experiments with different pool sizes and mixture contents were conducted to study the combustion behavior of pool fires in atmospheric conditions. The initial pool area of 0.25 m2, 0.66 m2, and 2.8 m2, the initial volume of fuel and time of burning process, and the initial gasoline thickness of 20 mm were determined in each experiment. The fire models are defined by the European standard EN 3 and were used to model fire of the class MB (model liquid fire for the fire area 0.25 m2), of the class 21B (model liquid fire for the fire area 0.66 m2), and 89B (model liquid fire for the fire area 2.8 m2). The fire models were used to class 21B and 89B for fuel by Standard EN 3. The flame geometrical characteristics were recorded by a CCD (charge-coupled device) digital camera. The results show turbulent flame with constant loss burning rate per area, different flame height, and different heat release rate. Regression rate increases linearly with increasing pans diameter. The results show a linear dependence of the HRR (heat release rate) depending on the fire area (average 2.6 times).
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PMID:Fire Size of Gasoline Pool Fires. 3193 75