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)

Malignant hyperthermia (MH) is a pharmacogenetic disorder that predisposes to a sometimes fatal hypermetabolic reaction to halogenated anaesthetics. MH is considered to originate from abnormal regulation of skeletal muscle Ca(2+) release. Current diagnosis of MH susceptibility (MHS) relies on in vitro contracture testing (IVCT) of skeletal muscle. The ryanodine receptor (RYR1) encoding the major Ca(2+) release channel in the skeletal muscle sarcoplasmic reticulum has been shown to be mutated in a number of MH pedigrees. The large Maori pedigree reported here is the largest MHS pedigree investigated to date and comprises five probands who experienced clinical episodes of MH and 130 members diagnosed by the IVCT. Sequencing of the 15 117 bp RYR1 cDNA in a MHS individual from this pedigree identified a novel C14477T transition that results in a Thr4826 to Ile substitution in the C-terminal region/transmembrane loop of the skeletal muscle ryanodine receptor. This is the first mutation in the RyR1 C-terminal region associated solely with MHS. Although linkage analysis showed strong linkage (max LOD, 11.103 at theta = 0.133) between the mutation and MHS in the pedigree using the standardized European IVCT phenotyping protocol, 22 MHS recombinants were observed. The relationship between the IVCT response and genotype was explored and showed that as IVCT diagnostic cut-off points were made increasingly stringent, the number of MHS discordants decreased with complete concordance between the presence or absence of the C14477T mutation and MHS and MH normal phenotypes, respectively, using a cut-off of 1.2 g tension at 2.0 mM caffeine and 1.8 g tension at 2.0% halothane. Many MHS pedigrees investigated have been excluded from linkage to the RYR1 gene on the basis of a small number of recombinants; however, the linkage analysis reported here suggests that other recombinant families excluded from linkage to the RYR1 gene may actually demonstrate linkage as the number of members tested within the pedigrees increases. The high number of discordants observed using the standardized diagnostic cut-off points is likely to reflect the presence of a second MHS susceptibility locus in the pedigree.
Hum Mol Genet 2000 Jun 12
PMID:A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. 1088 2

Since the role of sarcoplasmic reticulum (SR) in the E-C coupling of mammalian atrial cells has long been a subject of debate, biochemical, electrophysiological and immunological assays were performed in order to define and compare the properties of the Ca(2+)-release channel-ryanodine receptor (RyR)-from atrial and ventricular tissues. Cardiac SR preparations from human, canine and ovine tissues were compared using [(3)H]ryanodine binding, channel reconstitution into planar lipid bilayers and Western blot analysis involving RyR antibodies. [(3)H]ryanodine binding assays revealed a K(d)value of; 2.5 n M for all investigated cardiac tissues. Bound [(3)H]ryanodine was Ca(2+)-dependent with similar EC(50)values of 0.43, 0.49 and 0.79 microM for human atrium, canine ventricle and ovine atrium, respectively. However the density of binding sites was 4.5 times lower in atrial than in ventricular tissues. Beyond the presence of selective K(+)channels (gamma=188 pS) recorded in the SR enriched fraction of human atrium, the activity of a large conducting (gamma=671 pS) cationic channel was also observed. The latter displayed typical characteristics of Ca(2+)-release channels which were activated by 10 microM free [Ca(2+)] and 2 m M ATP. Western blot analysis revealed the presence of the RyR2 isoform in atrial and ventricular samples whereas no immunoreactivity was detected with specific RyR1 and RyR3 antibodies. Our results, obtained at the molecular level, are consistent with the presence of functional SR in human atrial cells. The human atrial Ca(2+)-release channel displays binding and regulating properties typical of the RyR2 isoform.
J Mol Cell Cardiol 2000 Nov
PMID:Characterization of the sarcoplasmic reticulum k(+) and Ca(2+)-release channel-ryanodine receptor-in human atrial cells. 1104 Jan 8

Central core disease (CCD) and nemaline myopathy (NM) are congenital myopathies for which differential diagnosis is often based on the presence either of cores or rods. Missense mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in some families with CCD. Mutations in the alpha-tropomyosin and alpha-actin genes have been associated with most dominant forms of NM. Analysis of the RYR1 cDNA in a French family identified a novel Y4796C mutation that lies in the C-terminal channel-forming domain of the RyR1 protein. This mutation was linked not only to a severe and penetrant form of CCD, but also to the presence of rods in the muscle fibres and to the malignant hyperthermia susceptibility (MHS) phenotype. The Y4796C mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. Expression of the mutant RYR1 cDNA produced channels with increased caffeine sensitivity and a significantly reduced maximal level of Ca(2+) release. Single-cell Ca(2+) analysis showed that the resting cytoplasmic level was increased by 60% in cells expressing the mutant channel. These data support the view that the rate of Ca(2+) leakage is increased in the mutant channel. The resulting chronic elevation in myoplasmic concentration is likely to be responsible for the severe expression of the disease. Haplotyping analysis indicated that the mutation arose as a neomutation in the proband. This first report of a neomutation in the RYR1 gene has strong implications for genetic linkage studies of MHS or CCD, two diseases characterized by a genetic heterogeneity.
Hum Mol Genet 2000 Nov 01
PMID:An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. 1106 19

Arrhythmogenic right ventricular dysplasia type 2 (ARVD2, OMIM 600996) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability and sudden death. The disease locus was mapped to chromosome 1q42--q43. We report here on the physical mapping of the critical ARVD2 region, exclusion of two candidate genes (actinin 2 and nidogen), elucidation of the genomic structure of the cardiac ryanodine receptor gene (RYR2) and identification of RYR2 mutations in four independent families. In myocardial cells, the RyR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RyR2 is the cardiac counterpart of RyR1, the skeletal muscle ryanodine receptor, involved in malignant hyperthermia (MH) susceptibility and in central core disease (CCD). The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene. The detection of RyR2 mutations causing ARVD2, reported in this paper, opens the way to pre-symptomatic detection of carriers of the disease in childhood, thus enabling early monitoring and treatment.
Hum Mol Genet 2001 Feb 01
PMID:Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). 1115 36

Polycyclic aromatic hydrocarbons are environmental pollutants known to be carcinogenic and immunotoxic. In intact cell assays, benzo[a]pyrene (B[a]P) disrupts Ca(2+) homeostasis in both immune and nonimmune cells, but the molecular mechanism is undefined. In this study, B[a]P and five metabolites are examined for their ability to alter Ca(2+) transport across microsomal membranes. Using a well-defined model system, junctional SR vesicles from skeletal muscle, we show that a single o-quinone metabolite of B[a]P, B[a]P-7,8-dione, can account for altered Ca(2+) transport across microsomal membranes. B[a]P-7,8-dione induces net Ca(2+) release from actively loaded vesicles in a dose-, time-, and Ca(2+)-dependent manner. In the presence of 5 microM extravesicular Ca(2+), B[a]P-7,8-dione exhibited threshold and EC(50) values of 0.4 and 2 microM, respectively, and a maximal release rate of 2 micromol of Ca(2+) min(-1) mg(-1). The mechanism by which B[a]P-7,8-dione enhanced Ca(2+) efflux was further investigated by measuring macroscopic fluxes and single RyR1 channels reconstituted in bilayer lipid membranes and direct measurements of SERCA catalytic activity. B[a]P-7,8-dione (< or = 20 microM) had no measurable effect on initial rates of Ca(2+) accumulation in the presence of ruthenium red to block ryanodine receptor (RyR1), nor did it alter Ca(2+)-dependent (thapsigargin-sensitive) ATPase activity. B[a]P-7,8-dione selectively altered the function of RyR1 in a time-dependent diphasic manner, first activating then inhibiting channel activity. Considering that RyR1 and its two alternate isoforms are broadly expressed in mammalian cells and their important role in Ca(2+)-signaling, the present results reveal a mechanism by which metabolic bioactivation of B[a]P may mediate RyR dysfunction of pathophysiological significance.
Mol Pharmacol 2001 Mar
PMID:A bioactive metabolite of benzo[a]pyrene, benzo[a]pyrene-7,8-dione, selectively alters microsomal Ca2+ transport and ryanodine receptor function. 1117 46

Skeletal muscle triadin is a sarcoplasmic reticulum (SR) membrane protein that had been shown to interact structurally and functionally at the cytoplasmic domain (amino acid residues 1-47) with the ryanodine receptor (RyR1), and to undergo phosphorylation by endogenous calmodulin protein kinase (CaM K II) in isolated terminal cisternae from rabbit fast-twitch muscle. Here we show that triadin cytoplasmic domain expressed as glutathione-S-transferase fusion protein, is a substrate of the protein kinase. This finding is corroborated by identification of a specific consensus sequence in the deduced amino sequence between residue 34 and 37 of triadin. Confirming the regulatory features of CaM K II, we show the phosphorylation of triadin cytoplasmic segment by the kinase, when converted to the autonomous form. We propose that triadin modulates RyR1 in a phosphorylation-dependent manner.
Mol Cell Biochem 2001 Jul
PMID:Phosphorylation of the triadin cytoplasmic domain by CaM protein kinase in rabbit fast-twitch muscle sarcoplasmic reticulum. 1168 15

Central core disease (CCD) is an autosomal dominant congenital myopathy. Diagnosis is based on the presence of cores in skeletal muscles. CCD has been linked to the gene encoding the ryanodine receptor (RYR1) and is considered to be an allelic disease of malignant hyperthermia susceptibility. However, the report of a recessive form of transmission together with a variable clinical presentation has raised the question of the genetic heterogeneity of the disease. Analyzing a panel of 34 families exclusively recruited on the basis of both clinically and morphologically expressed CCD, 12 different mutations of the C-terminal domain of RYR1 have been identified in 16 unrelated families. Morphological analysis of the patients' muscles showed different aspects of cores, all of them associated with mutations in the C-terminal region of RYR1. Furthermore, we characterized the presence of neomutations in the RyR1 gene in four families. This indicates that neomutations into the RyR1 gene are not a rare event and must be taken into account for genetic studies of families that present with congenital myopathies type 'central core disease'. Three mutations led to the deletion in frame of amino acids. This is the first report of amino acid deletions in RYR1 associated with CCD. According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1.
Hum Mol Genet 2001 Oct 15
PMID:Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. 1170 45

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.
Hum Mol Genet 2001 Dec 01
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

In skeletal muscle, L-type calcium channels (or dihydropyridine receptors, DHPRs) are coupled functionally to the calcium release channels of the sarcoplasmic reticulum (or ryanodine receptors, RyRs) within specialized structures called calcium release units (CRUs). The functional linkage requires a specific positioning of four DHPRs in correspondence of the four identical subunits of a single RyR type 1. Four DHPRs linked to the four binding sites of the RyR1 cytoplasmic domain (or foot), define the corners of a square, constituting a tetrad. RyRs self-assemble into ordered arrays and by associating with them, DHPRs also assemble into ordered arrays. The approximate location of the four DHPRs relative to the four identical subunits of a RyR-foot can be predicted on the basis of the relative position of tetrads and feet within the arrays. However, until recently one vital piece of information has been lacking: the orientation of the two arrays relative to one another. In this work we have defined the relative orientation of the RyR and DHPR arrays by directly superimposing replicas of rotary shadowed images of rows of feet, obtained from isolated SR vesicles, and replicas of tetrad arrays obtained by freeze-fracture. If the orientation for the two sets of images is carefully maintained, the superimposition provides specific constraints on the DHPR-RyR relative position.
J Mol Biol 2004 Sep 03
PMID:The relative position of RyR feet and DHPR tetrads in skeletal muscle. 1531 13

Patients with chronic diabetes mellitus usually develop reductions in rate and force of cardiac contractions. Since calcium-release channels (ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP(3)Rs)) play integral roles in effecting these processes, we rationalize that alterations in their expression may underlie these defects. To test this hypothesis, right atrial appendages were obtained from diabetic (65.0 +/- 4.5 years) and nondiabetic (56.2 +/- 2.6 years) patients undergoing coronary arterial by-pass grafting and reverse transcription-polymerase chain reactions were used to compare steady state levels of mRNA encoding the three major isoforms of RyRs and IP(3)Rs. In this study we did not detect either RyR1 or RyR3 in human atrial appendage. When compared with nondiabetic patients, mRNA encoding RyR2 from diabetic patients decreased by 74.2 +/- 6.2% (p < 0.01). Diabetes also significantly decreased steady-state levels of mRNA encoding the IP(3)Rs in human atrial appendage. IP(3)R1 decreased by 24.2 +/- 4.6%, IP(3)R2 decreased by 63.0 +/- 4.6% and IP(3)R3 decreased by 55.5 +/- 6.5%. Since a reduction in steady-state mRNA is usually indicative of a decrease in protein levels, these data suggest that the decrease in chronotropy and inotropy seen in chronic diabetic patients may be due in part to a decrease in expression of calcium-release channels.
Mol Cell Biochem 2004 Aug
PMID:Diabetes decreases mRNA levels of calcium-release channels in human atrial appendage. 1552 75


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