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

Malignant hyperthermia (MH) is a potentially fatal, inherited pharmacogenetic disorder characterised by a dysfunction of the intracellular calcium regulation. Linkage to DNA markers from the chromosome 19q12-13.2 region and the MHS-phenotype (MH susceptible) has been shown in about 50% of families with a history of MH. The ryanodine receptor gene encoding the human skeletal muscle ryanodine receptor has been localised to the chromosome 19q13.1-13.2 region. The ryanodine receptor, which is an intracellular calcium release channel, has been proposed to be one of the candidate structures for the MH defect. At present, eight different single point mutations have been identified in the human skeletal muscle ryanodine receptor gene in families with disposition to MH. The incidence of the various mutations has been reported as 2-10% each. A combination of different mutations within one pedigree has not been demonstrated. A few years ago, linkage of the MHS-phenotype to DNA markers from the chromosome 17q11.2-24 region was published by an American group. However, this observation has not been confirmed in any of the several European families susceptible to MH. Genes encoding for subunits of the dihydropyridine receptor and the sodium channel of the human skeletal muscle have been found to be located in the chromosome 17q11.2-24 region which, in fact, could be additional candidates for the MH defect. The dihydropyridine receptor is linked to the ryanodine receptor and involved in the calcium regulation of skeletal muscle. Very recent studies have shown linkage to DNA markers from chromosome 7q- and chromosome 3q13.1 regions and the MHS phenotype in two distinct families with history of MH. However, the relevance of this observation is so far unknown. At present, unambiguous preoperative screening of MH disposition based on molecular genetic characteristics is not available because of the enormous heterogeneity of the human MH syndrome. Thus, the halothane-caffeine in-vitro contracture test according to the standard protocol of the "European MH Group" must be performed in order to discover MH susceptibility.
 ...
PMID:[What significance to genotype changes have in diagnosis of malignant hyperthermia?]. 896 26

Malignant hyperthermia (MH) is an autosomal dominant disorder which is potentially lethal in susceptible individuals on exposure to commonly used inhalational anaesthetics and depolarising muscle relaxants. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. Susceptibility was first localised to chromosome 19q13.1 and the skeletal muscle ryanodine receptor, RYR1 (the calcium release channel of the sarcoplasmic reticulum). Defects in this gene have been identified which cosegregate with the MHS phenotype and evidence as to their potential causal roles has accumulated. MH has, however, been shown to be genetically heterogeneous, additional loci on chromosomes 3q, 17q and 7q being proposed. Pedigrees remain in Europe where linkage status is still unclear. In a collaborative search of the human genome conducted with three pedigrees whose disease status was classified according to the European IVCT protocol we have evidence to suggest that at least two further loci exist for MH susceptibility. One of these locates to chromosome 1q, the site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the dihydropyridine receptor. The second region resides on chromosome 5p to where no known candidate has been mapped to date. The third family exhibited inconclusive results which suggests the existence of at least one other locus. This study adds to the evidence for considerable genetic heterogeneity in MH and will provide a route to further our understanding of the molecular pathology of the condition.
 ...
PMID:A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. 917 45

Malignant hyperthermia (MH) is an autosomal dominant genetic condition that presents in susceptible people undergoing general anaesthesia. The clinical disorder is a major cause of anaesthetic morbidity and mortality. The UK Malignant Hyperthermia Group has performed genetic linkage analysis on 20 large, well defined malignant hyperthermia families, using hypervariable markers on chromosome 19q13.1, including the candidate MH gene RYR1, the gene coding for the skeletal muscle ryanodine receptor protein. The results were analysed using LINKAGE to perform two point and multipoint lod scores, then HOMOG to calculate levels of heterogeneity. The results clearly showed genetic heterogeneity between MH families; nine of the families gave results entirely consistent with linkage to the region around RYR1 while the same region was clearly excluded in three families. In the remaining eight MHS families there were single recombinant events between RYR1 and MH susceptibility. HOMOG analysis was of little added benefit in determining the likelihood of linkage to RYR1 in these families. This confirmation of the presence of heterogeneity in the UK MH population, along with the possibility of the presence of two MH genes in some pedigrees, indicates that it would be premature and potentially dangerous to offer diagnosis of MH by DNA based methods at this time.
 ...
PMID:Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families. 954 Nov 2

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.
 ...
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

A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
 ...
PMID:Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. 2801 84