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)

A locus for malignant hyperthermia susceptibility (MHS) has been localized on chromosome 19q12-13.2, while at the same time the gene encoding the skeletal muscle ryanodine receptor (RYR1) also has been mapped to this region and has been found to be tightly linked to MHS. RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients. Here we report the results of a linkage study done with 19q12-13.2 markers, including the RYR1 cDNA, in two Bavarian families with MHS. In one of the families, three unambiguous recombination events between MHS and the RYR1 locus were found. In the second family only one informative meiosis was seen with RYR1. However, segregation analysis with markers for D19S75, D19S28, D19S47, CYP2A, BCL3, and APOC2 shows that the crossovers in the first family involve the entire haplotype defined by these markers flanking RYR1 and, furthermore, reveals multiple crossovers between these haplotypes and MHS in the second family. In these families, pairwise and multipoint lod scores below -2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus. Our findings thus strongly suggest genetic heterogeneity of the MHS trait and prompt the search for another MHS locus.
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PMID:Evidence for genetic heterogeneity of malignant hyperthermia susceptibility. 159 99

Malignant hyperthermia (MH) is a devastating, potentially lethal response to anesthetics that occurs in genetically predisposed individuals. The skeletal muscle ryanodine receptor (RYR1) gene has been linked to porcine and human MH. Furthermore, a Cys for Arg substitution tightly linked to, and potentially causative of, porcine MH has been identified in the ryanodine receptor. Analysis of 35 human families predisposed to malignant hyperthermia has revealed the presence, and cosegregation with phenotype, of the corresponding substitution in a single family. This substitution, by analogy to the findings in pig, may be causal for predisposition to MH in this family.
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PMID:A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. 177 74

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluster.
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PMID:Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. 784 12

A total of 392 pigs of European Landrace and Pietrain origin segregating for malignant hyperthermia (MH) were genotyped using a polymerase chain reaction (PCR)/restriction endonuclease test for the C-T mutation at nucleotide (nt) 1843 in the skeletal muscle ryanodine receptor (RYR1) gene, earlier identified as the causal mutation for MH. All pigs had been halothane tested and genotyped at linked polymorphic marker loci. There was complete correlation between MH status of the 392 animals, as diagnosed by a combination of the halothane challenge test with S, GPI, H, A1BG, PGD haplotyping, and the DNA-based test. DNA-based detection of the MH status in 238 MH-susceptible heterozygous (N/n) and homozygous (n/n) pigs was shown to be accurate, eliminating the 2% diagnostic error that is associated with the halothane challenge test. The mutation was also associated with an allele of a polymorphic microsatellite (ETH5 001) at the RYR1 locus.
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PMID:Co-segregation of the malignant hyperthermia and the Arg615-Cys615 mutation in the skeletal muscle calcium release channel protein in five European Landrace and Pietrain pig breeds. 794 85

Analysis of the primary structure of the rabbit skeletal muscle ryanodine receptor led to the identification of two molecules of 5032 and 5037 residues, respectively. Such a sequence discrepancy is likely to be due to the alternative splicing of a 15 bp exon (1) encoding a 5 amino acid insertion (Ala-Gly-Asp-Ala-Gln) after residue 3479. By using PCR on first strand cDNA, we searched for the 15 base pair insertion in the ryanodine receptor mRNA from adult slow- and fast-twitch skeletal muscle, as well as from fast-muscles, at various stages of post-natal development. All rabbit skeletal muscle mRNAs, regardless of their developmental stage and twitch properties, contain two RYR transcripts, suggesting the coexistence of two RYR isoforms in mammalian skeletal muscle.
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PMID:Identification of two ryanodine receptor transcripts in neonatal, slow-, and fast-twitch rabbit skeletal muscles. 794 21

In the present study, we have identified calmodulin binding sequences in the skeletal muscle ryanodine receptor Ca2+ release channel. Ligand overlays on RYR fusion proteins indicate that the skeletal muscle RYR contains three calmodulin binding regions defined by residues 2937-3225, 3546-3655, and 4425-4621. The RYR fusion protein PC28 (residues 2937-3225) bound calmodulin in the presence of EGTA and Ca2+, while RYR fusion protein PC26 (residues 3546-3655) exhibited strong calmodulin binding at 10 microM Ca2+. The RYR fusion protein PC15 (residues 4425-4621) did not bind calmodulin in the presence of either EGTA or 10-50 microM Ca2+. In the presence of 100-500 microM Ca2+, the RYR fusion protein PC15 exhibited an affinity for calmodulin of approximately 50 nM. Peptides RYR1 PM2 (residues 3610-3629) and RYR1 PM3 (4534-4552) encompassing putative RYR-calmodulin binding sites were synthesized. The synthetic peptides interacted directly with dansylcalmodulin as demonstrated by their capacity to affect the fluorescence emission of dansylcalmodulin. Missense mutation analysis indicates that the Lys and Arg residues are essential for calmodulin binding to the synthetic peptide RYR1 PM3. The RYR calmodulin binding site defined by peptide PM3 lies in the myoplasmic loop 2, a few residues upstream of the putative transmembrane segment M5; the other two calmodulin binding sites are next to the putative transmembrane segments M' and M''. Thus, the effect of calmodulin on Ca2+ release might involve the regulation of the putative transmembrane segments M5, M', and M''.
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PMID:Identification and characterization of three calmodulin binding sites of the skeletal muscle ryanodine receptor. 804 9

Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features. A close association with malignant hyperthermia (MH) has been identified. Since MH and CCD genes have been linked to the skeletal muscle ryanodine receptor (RYR1) gene, cDNA sequence analysis was used to search for a causal RYR1 mutation in a CCD individual. The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD.
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PMID:A mutation in the human ryanodine receptor gene associated with central core disease. 822 Apr 22

The skeletal muscle ryanodine receptor (RYR1) belongs to a family of calcium release channels that are expressed in different tissues. The RYR1 gene is one of the largest genes characterized, so far, containing a 15253 nucleotide ORF in swine. To study the genomic organization of the porcine skeletal muscle ryanodine receptor gene we have isolated seven genomic fragments spanning 72.7 kb of chromosomal DNA of chromosome 6q12. This region harbours exons 1 to 71 coding for 3538 amino acids (69.6%) of the ryanodine receptor 1.
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PMID:The porcine skeletal muscle ryanodine receptor gene structure coding region 1 to 10614 harbouring 71 exons. 893 69

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.
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PMID:[What significance to genotype changes have in diagnosis of malignant hyperthermia?]. 896 26

The neuroleptic malignant syndrome (NMS) is a drug-induced disease caused by neuroleptics, but the pathogenesis of NMS is unknown. Since NMS is similar to malignant hyperthermia (MH) in clinical features and treatment, 6 mutations in the skeletal muscle ryanodine receptor (RYR1) gene, which were associated with MH, were investigated in unrelated NMS patients by single-strand conformation polymorphism analysis (SSCP). As a result, MH-susceptible RYR1 mutations were not detected in our NMS patients. A single base substitution, C7278T, was detected in one patient whose serum CPK level was repetitively elevated, but his other major symptoms did not fulfil the clinical criteria for NMS. Our results do not support the association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated with malignant hyperthermia.
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PMID:No association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated malignant hyperthermia. 898 16


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