Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia susceptibility (MHS), a skeletal muscle disorder, is mostly inherited as an autosomal dominant trait. Exposure of susceptible individuals to volatile halogenated anaesthetics can lead to a MH episode resulting in irreversible tissue damages or to the patient's death if not immediately reversed by dantrolene treatment. A MH episode is characterised by a combination of hyperthermia, skeletal muscle rigidity and hypermetabolism. Porcine stress syndrome has proved to be a valuable model for physiopathological studies of MHS. Malignant hyperthermia syndrome is associated with a failure of the calcium homeostasis in muscular fibres. Dysfunction of the calcium channels: the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR), which are involved in the release of the Ca2+ stored in sarcoplasmic reticulum has been clearly demonstrated. A biochemical test based on the analysis of the in vitro contracture response of muscular fibres to caffeine and halothane was developed to define the MHS status of patients. Although the genetic analysis of MHS has beneficiated from recent progresses, genetic testing is still far to answer to all testing situations. If in swine, hyperthermia syndrome was always associated with a unique mutation of the RyR1 gene, genetic analysis is far more complicated in human: i) more than 20 different MHS mutations in the RyR1 gene have been described; ii) a mutation of the gene encoding the dihydropyridine receptor has been identified; iii) 4 other potential MHS loci have been reported.
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PMID:[Biology of malignant hyperthermia: a disease of the calcium channels of the skeletal muscle]. 1076 Jul 1

Localized distribution of malignant hyperthermia (MH) and central core disease (CCD) mutations in N-terminal and central domains of the ryanodine receptor suggests that the interaction between these domains may be involved in Ca(2+) channel regulation. To test this hypothesis, we investigated the effects of a new synthetic domain peptide DP4 corresponding to the Leu(2442)-Pro(2477) region of the central domain. DP4 enhanced ryanodine binding and induced a rapid Ca(2+) release. The concentration for half-maximal activation by agonists was considerably reduced in the presence of DP4. These effects of DP4 are analogous to the functional modifications of the ryanodine receptor caused by MH/CCD mutations (viz. hyperactivation of the channel and hypersensitization of the channel to agonists). Replacement of Arg of DP4 with Cys, mimicking the in vivo Arg(2458)-to-Cys(2458) mutation, abolished the activating effects of DP4. An N-terminal domain peptide DP1 (El-Hayek, R., Saiki, Y., Yamamoto, T., and Ikemoto, N. (1999) J. Biol. Chem. 274, 33341-33347) shows similar activation/sensitization effects. The addition of both DP4 and DP1 produced mutual interference of their activating functions. We tentatively propose that contact between the two (N-terminal and central) domains closes the channel, whereas removal of the contact by these domain peptides or by MH/CCD mutations de-blocks the channel, resulting in hyperactivation/hyper-sensitization effects.
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PMID:Postulated role of interdomain interaction within the ryanodine receptor in Ca(2+) channel regulation. 1076 78

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation-contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility.
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PMID:Ryanodine receptor mutations in malignant hyperthermia and central core disease. 1079 Feb 2

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.
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PMID:A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. 1088 2

Based on the gene-related function and molecular structure of various receptors, neurological receptor diseases were reviewed from both the immunologic and genetic perspectives. The nicotinic acetyl-choline receptor (AChR), ryanodine receptor (RyR), omega-conotoxin receptor (P/Q-type voltage-gated calcium channel), dihydropyridine receptor (L-type voltage gated calcium channel), and androgen receptor have been found to be affected by autoantibodies and/or genetic anomalies. They reflect on various neurological diseases such as myasthenia gravis, congenital myasthenic syndrome, malignant hyperthermia and central core disease, paraneoplastic myasthenic syndrome, hereditary migraine and ataxias, hypokalemic periodic paralysis, and bulbospinal muscular atrophy. The interaction of calcitonin gene-related peptide with its receptor tends to compensate the dysfunction caused by antibodies to AChR and RyR. One should look for cancers or genetic disorders in the case of the receptor disease implicated in calcium channel function. Recent advances in search for the etiology of these diseases from the standpoints of immunology and genetics have opened an avenue in understanding the functional structure of receptors and the molecular sites responsible for receptor diseases.
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PMID:[Receptor diseases in the field of neurology]. 1089 86

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.
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PMID:Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. 1089 34

Ca2+ inward current and fura-2 Ca2+ transients were simultaneously recorded in porcine myotubes. Myotubes from normal pigs and cells from specimens homozygous for the Arg615Cys (malignant hyperthermia) mutation of the skeletal muscle ryanodine receptor RyR1 were investigated. We addressed the question whether this mutation alters the voltage dependence of Ca2+ release from the sarcoplasmic reticulum. The time course of the total flux of Ca2+ into the myoplasm was estimated. Analysis showed that the largest input Ca2+ flux occurred immediately after depolarization. Amplitude and time course of the Ca2+ flux at large depolarizations were not significantly different in the Arg615Cys myotubes. Ca2+ release from the sarcoplasmic reticulum was activated at more negative potentials than the L-type Ca2+ conductance. In the controls, the potentials for half-maximal activation V 1/2 were -9.0mV and 16.5 mV, respectively. In myotubes expressing the Arg615Cys mutation, Ca2+ release was activated at significantly lower depolarizing potentials (V = -23.5 mV) than in control myotubes. In contrast, V of conductance activation (13.5 mV) was not significantly different from controls. The specific shift in the voltage dependence of Ca2+ release caused by this mutation can be well described by altering a voltage-independent reaction of the ryanodine receptor that is coupled to the voltage-dependent transitions of the L-type Ca2+ channel.
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PMID:Malignant hyperthermia mutation Arg615Cys in the porcine ryanodine receptor alters voltage dependence of Ca2+ release. 1092 99

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue.
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PMID:The role of sphingolipids in the control of skeletal muscle function: a review. 1093 63

The excitation-contraction-relaxation cycle of skeletal muscle fibres depends on the finely tuned interplay between the voltage-sensing dihydropyridine receptor, the junctional ryanodine receptor Ca2+-release channel and the sarcoplasmic reticulum Ca2+-ATPase. Inherited diseases of excitation-contraction coupling and muscle relaxation such as malignant hyperthermia, central core disease, hypokalemic periodic paralysis or Brody disease are caused by mutations in these Ca2+-regulatory elements. Over twenty different mutations in the Ca2+-release channel are associated with susceptibility to the pharmacogenetic disorder malignant hyperthermia. Other mutations in the ryanodine receptor trigger central core disease. Primary abnormalities in the alpha-1 subunit of the dihydropyridine receptor underlie the molecular pathogenesis of both hypokalemic periodic paralysis and certain forms of malignant hyperthermia. Some cases of the muscle relaxation disorder named Brody disease were demonstrated to be based on primary abnormalities in the Ca2+-ATPase. Since a variety of other sarcoplasmic reticulum proteins modulate the activity of the voltage sensor, Ca2+-release channel and ion-binding proteins, mutations in these Ca2+-regulatory muscle components might be the underlying cause for novel, not yet fully characterized, genetic muscle disorders. The cell biological analysis of knock-out mice has been helpful in evaluating the biomedical consequences of defects in ion-regulatory muscle proteins.
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PMID:The role of ion-regulatory membrane proteins of excitation-contraction coupling and relaxation in inherited muscle diseases. 1114 21

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.
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PMID:Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). 1115 36


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