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)

To explain the mechanism of pathogenesis of channel disorder in MH (malignant hyperthermia), we have proposed a model in which tight interactions between the N-terminal and central domains of RyR1 (ryanodine receptor 1) stabilize the closed state of the channel, but mutation in these domains weakens the interdomain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu2442-Pro2477 of the central domain, also weakens the domain interaction and produces MH-like channel destabilization, whereas an MH mutation (R2458C) in DP4 abolishes these effects. Thus DP4 and its mutants serve as excellent tools for structure-function studies. Other MH mutations have been reported in the literature involving three other amino acid residues in the DP4 region (Arg2452, Ile2453 and Arg2454). In the present paper we investigated the activity of several mutants of DP4 at these three residues. The ability to activate ryanodine binding or to effect Ca2+ release was severely diminished for each of the MH mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the peptide has two a-helical regions. It is apparent that the MH mutations are clustered at the C-terminal end of the first helix. The data in the present paper indicates that mutation of residues in this region disrupts the interdomain interactions that stabilize the closed state of the channel.
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PMID:Malignant hyperthermia mutation sites in the Leu2442-Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area. 1695 17

We have demonstrated recently that CICR (Ca2+-induced Ca2+ release) activity of RyR1 (ryanodine receptor 1) is held to a low level in mammalian skeletal muscle ('suppression' of the channel) and that this is largely caused by the interdomain interaction within RyR1 [Murayama, Oba, Kobayashi, Ikemoto and Ogawa (2005) Am. J. Physiol. Cell Physiol. 288, C1222-C1230]. To test the hypothesis that aberration of this suppression mechanism is involved in the development of channel dysfunctions in MH (malignant hyperthermia), we investigated properties of the RyR1 channels from normal and MHS (MH-susceptible) pig skeletal muscles with an Arg615-->Cys mutation using [3H]ryanodine binding, single-channel recordings and SR (sarcoplasmic reticulum) Ca2+ release. The RyR1 channels from MHS muscle (RyR1MHS) showed enhanced CICR activity compared with those from the normal muscle (RyR1N), although there was little or no difference in the sensitivity to several ligands tested (Ca2+, Mg2+ and adenine nucleotide), nor in the FKBP12 (FK506-binding protein 12) regulation. DP4, a domain peptide matching the Leu2442-Pro2477 region of RyR1 which was reported to activate the Ca2+ channel by weakening the interdomain interaction, activated the RyR1N channel in a concentration-dependent manner, and the highest activity of the affected channel reached a level comparable with that of the RyR1MHS channel with no added peptide. The addition of DP4 to the RyR1MHS channel produced virtually no further effect on the channel activity. These results suggest that stimulation of the RyR1MHS channel caused by affected inter-domain interaction between regions 1 and 2 is an underlying mechanism for dysfunction of Ca2+ homoeostasis seen in the MH phenotype.
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PMID:Postulated role of interdomain interaction between regions 1 and 2 within type 1 ryanodine receptor in the pathogenesis of porcine malignant hyperthermia. 1710 40

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered in susceptible individuals by inhalation anesthetics and depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% of cases studied to date. Using double-barreled Ca(2+) microelectrodes in myotubes expressing wild-type RyR1 ((WT)RyR1) or RyR1 with one of four common MH mutations ((MH)RyR1), we measured resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Changes in resting [Ca(2+)](i) produced by several drugs known to modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the (MH)RyR1s had a 2.0- to 3.7-fold higher resting [Ca(2+)](i) than those expressing (WT)RyR1. Exposure of myotubes expressing (MH)RyR1s to ryanodine (500 microM) or (2,6-dichloro-4-aminophenyl)isopropylamine (FLA 365; 20 microM) had no effects on their resting [Ca(2+)](i). However, when myotubes were exposed to bastadin 5 alone or to a combination of ryanodine and bastadin 5, the resting [Ca(2+)](i) was significantly reduced (P < 0.01). Interestingly, the percent decrease in resting [Ca(2+)](i) in myotubes expressing (MH)RyR1s was significantly greater than that for (WT)RyR1. From these data, we propose that the high resting myoplasmic [Ca(2+)](i) in (MH)RyR1 expressing myotubes is due in part to a related structural conformation of (MH)RyR1s that favors "passive" calcium leak from the sarcoplasmic reticulum.
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PMID:Elevated resting [Ca(2+)](i) in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR. 1718 26

A novel single-nucleotide deletion in exon 100 of the RYR1 gene, corresponding to deletion of nucleotide 14,510 in the human RyR1 mRNA (c14510delA), was identified in a man with malignant hyperthermia and in his two daughters who were normal for malignant hyperthermia. This deletion results in a RyR1 protein lacking the last 202 amino acid residues. All three subjects heterozygotic for the mutated allele presented with a prevalence of type 1 fibres with central cores, although none experienced clinical signs of myopathy. Expression of the truncated protein resulted in non-functional RYR1 calcium release channels. Expression of wild-type and RyR1(R4836fsX4838) proteins resulted in heterozygotic release channels with overall functional properties similar to those of wild-type RyR1 channels. Nevertheless, small differences in sensitivity to calcium and caffeine were observed in heterotetrameric channels, which also presented an altered assembly/stability in sucrose-gradient centrifugation analysis. Altogether, these data suggest that altered RYR1 tetramer assembly/stability coupled with subtle chronic changes in Ca2+ homoeostasis over the long term may contribute to the development of core lesions and incomplete malignant hyperthermia susceptibility penetrance in individuals carrying this novel RYR1 mutation.
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PMID:A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres. 1729 38

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.
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PMID:Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. 1748 90

Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.
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PMID:Central core disease. 1750 18

Multi-minicore Disease (MmD) is a recessively inherited neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown. Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background. Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis; calcium-binding motifs within the selenoprotein N protein also suggest a possible role in calcium handling. The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms. In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.
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PMID:Multi-minicore Disease. 1763 Oct 35

Ryanodine receptor (RyR) is a Ca(2+) channel that mediates Ca(2+) release from intracellular stores. Altered Ca(2+) homeostasis in skeletal muscle which usually occurs as a result of point mutations in type 1 RyR1 (RyR1) is a key molecular event triggering malignant hyperthermia (MH). There are three RyR isoforms, and we herein show, for the first time, that human dendritic cells (DCs) preferentially express RyR1 mRNA among them. The RyR activator, 4-chloro-m-cresol (4CmC), induced Ca(2+) release in DCs, and this response was eliminated by dantrolene, an inhibitor of the RyR1, and was unaffected by xestospongin C, a selective inhibitor of IP(3) receptor. Activation of RyR1 reduced LPS-induced IL-10 production, promoted the expression of HLA-DR and CD86, and thereby exhibited an improved capacity to stimulate allogeneic T cells. These findings demonstrate that RyR1-mediated calcium signaling modifies diverse DC responses and suggest the feasibility of using DC preparations for the diagnosis of MH.
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PMID:Identification of functional type 1 ryanodine receptors in human dendritic cells. 1770 69

Myotubes expressing wild type RyR1 (WT) or RyR1 with one of three malignant hyperthermia mutations R615C, R2163C, and T4826I (MH) were exposed sequentially to 60 mm KCl in Ca(2+)-replete and Ca(2+)-free external buffers (Ca+ and Ca-, respectively) with 3 min of rest between exposures. Although the maximal peak amplitude of the Ca(2+) transients during K(+) depolarization was similar for WT and MH in both external buffers, the rate of decay of the sustained phase of the transient during K(+) depolarization (decay rate) in Ca+ was 50% slower for MH. This difference was eliminated in Ca-, and the relative decay rates were faster for both genotypes than in Ca+. The integrated Ca(2+) transient in Ca-compared with Ca+ was reduced by 50-60% for MH and 20% for WT. The decay rate was not affected by [K(+)] x [Cl(-)] product or NiCl(2) (2 mm) supplementation of Ca-. The addition of La(2+) (0.1 mm), or SKF 96365 (20 microm) to Ca+ significantly accelerated decay rates for both WT and MH, but their effect was significantly greater in MH. Nifedipine (1 microm) had no effect, suggesting that the mechanism for this difference was not a reduction in L-type Ca(2+) channel Ca(2+) current. These data strongly suggest: 1) the decay rate in skeletal myotubes is related in part to Ca(2+) entry through the ECCE channel; 2) the MH mutations enhance ECCE compared with wild type; and 3) the increased Ca(2+) entry might play a significant role in the pathophysiology of MH.
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PMID:Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. 1794 9

Ryanodine receptor (RyR) is the Ca(2+)-induced Ca(2+) release channel in cells. RyR1 and RyR2 are its isoforms expressed in the skeletal and cardiac muscles, respectively. Their missense mutations, which are clustered in three regions that correspond to each other, cause hereditary disorders such as malignant hyperthermia and central core disease in skeletal muscle and catecholaminergic polymorphic ventricular tachycardia in cardiac muscle. Their pathogeneses, however, are not well understood. The following hypotheses are favorably discussed in this article: phenotypes with RyR1 and RyR2 mutations are mainly caused by dysregulations of their functions through the interdomain interaction and luminal Ca(2+), respectively.
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PMID:Distinct mechanisms for dysfunctions of mutated ryanodine receptor isoforms. 1806 58


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