scholarly journals Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test

2016 ◽  
Vol 116 (4) ◽  
pp. 566-568 ◽  
Author(s):  
N Roux-Buisson ◽  
N Monnier ◽  
E Sagui ◽  
A Abriat ◽  
C Brosset ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Positive Response ◽  
Heat Stroke ◽  
Receptor Type ◽  
Exertional Heat Stroke ◽  
In Vitro Contracture Test

Several Ryanodine Receptor Type 1 Gene Mutations of p.Arg2508 Are Potential Sources of Malignant Hyperthermia

2015 ◽  
Vol 121 (4) ◽  
pp. 994-1000 ◽  
Author(s):  
Hirotsugu Miyoshi ◽  
Toshimichi Yasuda ◽  
Sachiko Otsuki ◽  
Takashi Kondo ◽  
Toshiaki Haraki ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Gene Mutations ◽  
Receptor Type ◽  
Potential Sources

Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis

2001 ◽  
Vol 94 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Frank Wappler ◽  
Marko Fiege ◽  
Markus Steinfath ◽  
Kamayni Agarwal ◽  
Jens Scholz ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Receptor Gene ◽  
Heat Stroke ◽  
Histologic Examination ◽  
In Vitro Contracture Test ◽  
Genetic Abnormalities ◽  
History Of ◽  
Exercise Induced ◽  
Muscle Biopsies

Background Malignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress. Methods Twelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens. Results Ten ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient. Conclusions Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.

scholarly journals Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

2011 ◽  
Vol 58 (6) ◽  
pp. 504-513 ◽  
Author(s):  
Natasha Kraeva ◽  
Sheila Riazi ◽  
Julian Loke ◽  
Wanda Frodis ◽  
Mary Lou Crossan ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Gene Mutations ◽  
Receptor Type

scholarly journals Scanning for Mutations of the Ryanodine Receptor (RYR1) Gene by Denaturing HPLC: Detection of Three Novel Malignant Hyperthermia Alleles

2003 ◽  
Vol 49 (5) ◽  
pp. 761-768 ◽  
Author(s):  
Angela Tammaro ◽  
Adele Bracco ◽  
Santolo Cozzolino ◽  
Maria Esposito ◽  
Antonietta Di Martino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Sudden Increase ◽  
Gene Encoding ◽  
In Vitro Contracture Test ◽  
Ryr1 Gene ◽  
Molecular Tests ◽  
Anesthetic Agents

Abstract Background: Malignant hyperthermia (MH) is a fatal autosomal dominant pharmacogenetic disorder characterized by skeletal muscle hypertonicity that causes a sudden increase in body temperature after exposure to common anesthetic agents. The disease is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. To date, at least 42 RYR1 mutations have been described that cause MH and/or central core disease. Because the RYR1 gene is huge, containing 106 exons, molecular tests have focused on the regions that are more frequently mutated. Thus the causative defect has been identified in only a fraction of families as linked to chromosome 19q, whereas in others it remains undetected. Methods: We used denaturing HPLC (DHPLC) to analyze the RYR1 gene. We set up conditions to scan the 27 exons to identify both known and unknown mutations in critical regions of the protein. For each exon, we analyzed members from 52 families with positive in vitro contracture test results, but without preliminary selection by linkage analysis. Results: We identified seven different mutations in 11 MH families. Among them, three were novel MH alleles: Arg44Cys, Arg533Cys, and Val2117Leu. Conclusion: Because of its sensitivity and speed, DHPLC could be the method of choice for the detection of unknown mutations in the RYR1 gene.

Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture

1998 ◽  
Vol 89 (3) ◽  
pp. 693-698. ◽  
Author(s):  
Richard L. Brooksbank ◽  
Margaret E. Badenhorts ◽  
Hyam Isaacs ◽  
Nerina Savage
Keyword(s):  
Carbon Dioxide ◽  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Type ◽  
Muscle Strip ◽  
Healthy Human ◽  
Healthy Persons

Background FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. Methods Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. Results Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane. Conclusions The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

scholarly journals Heat hypersensitivity of ryanodine receptor type 1 mutants implicated in malignant hyperthermia

2020 ◽  
Author(s):  
Kotaro Oyama ◽  
Vadim Zeeb ◽  
Toshiko Yamazawa ◽  
Takashi Murayama ◽  
Hideto Oyamada ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Positive Feedback ◽  
Intracellular Signaling ◽  
Feedback Loop ◽  
Local Heat ◽  
Receptor Type ◽  
Positive Feedback Loop ◽  
Hek 293

AbstractCellular heat-sensing is a universal strategy for avoiding thermal damage and adapting to environments by regulating thermogenic activities. If heat-sensing results in the acceleration of processes governing cellular thermogenesis, hyperthermia can occur. However, how this positive feedback loop contributes to hyperthermia development, especially the gap between heat-sensing and thermogenesis, remains largely unknown. Here, we show that an optically controlled local heat pulse induces an intracellular Ca2+ burst in cultured HEK 293 cells overexpressing ryanodine-receptor-type-1 (RyR1) mutants related to the life-threatening illness malignant hyperthermia (MH), and that the Ca2+ burst originates from heat-induced Ca2+-release (HICR) because of the mutant channels’ heat hypersensitivity. Furthermore, the heat hypersensitivity of the four RyR1 mutants was ranked, highlighting the complexity of MH. Our findings reveal the novel cellular heat-sensing mechanism, HICR, is essential for the functional positive feedback loop causing MH, suggesting a well-tuned HICR is fundamental for heat-mediated intracellular signaling.

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