Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47

Migita, Takako; Mukaida, Keiko; Hamada, Hiroshi; Yasuda, Tomoo; Haraki, Toshiaki; Nishino, Ichizo; Murakami, Nobuyuki; Kawamoto, Masashi

doi:10.1007/s00540-009-0746-3

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…His mother, patient number 18, had no identifiable mutations in RYR1 20 . The clinical presentation of patient number 2, suspected myopathy, had been reported previously 21 .…”

Section: Patientsmentioning

confidence: 88%

“…Not all RYR1 mutations cause MH, and several studies have shown that some RYR1 mutations are actually hyposensitive to RYR1 activators 29,30 . We did not perform a genetic analysis on all of the patients enrolled in this study, but three of the study subjects had undergone RYR1 analysis as part of earlier studies 20,21 . Patient number 18, the parent of an individual with a documented episode of MH, carried no mutations of RYR1, but two causative mutations (p.L4838V and p.R2508C) were identified in patients number 1 and 2, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Patients numbers 5 and 30 were brothers. Only three patients (numbers 1, 2 and 18) had undergone RYR1 gene analysis in a previous study 20,21 . The p.L4838V mutation was identified in patient number 1 and the p.R2508C mutation was identified in patient number 2.…”

Section: Patientsmentioning

confidence: 99%

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Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Kobayashi

Mukaida

Migita

et al. 2011

Anaesth Intensive Care

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Malignant hyperthermia is a life-threatening condition caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Identifying patients predisposed to malignant hyperthermia is done through the Ca-induced Ca release test in Japan. We examined the intracellular calcium concentration in human cultured muscle cells and compared the sensitivity of myotubes to ryanodine receptor type 1 activators based on the Ca-induced Ca release rate. We assessed the utility of this method as an identifying test for predisposition to malignant hyperthermia. Muscle specimens were obtained from 34 individuals undergoing the Ca-induced Ca release test. We cultured myotubes from residual material and monitored changes in intracellular calcium concentration after exposure to the ryanodine receptor type 1 activators caffeine, halothane and 4-chloro-m-cresol by measuring fura-2 fluorescence. We determined the half maximal effective concentrations (EC 50) for the test compounds in each myotube and calculated cutoff points using receiver operating characteristic curves. Seventeen patients each were classified into the accelerated and non-accelerated groups based on their Ca-induced Ca release rate. The EC 50 values for caffeine, halothane and 4-chloro-m-cresol of the accelerated group were significant lower than those of the nonaccelerated group (P <0.001, P <0.001 and P <0.001, respectively). The calculated cutoff points of EC 50 values for caffeine, halothane and 4-CmC were 3.62 mM, 2.28 mM and 197 μM, respectively. An increased sensitivity to ryanodine receptor type 1 activators was seen in myotubes in the accelerated group. This functional test on human cultured myotubes indicates that the alteration of their intracellular Ca 2+ homeostasis may identify the predisposition to malignant hyperthermia.

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“…His mother, patient number 18, had no identifiable mutations in RYR1 20 . The clinical presentation of patient number 2, suspected myopathy, had been reported previously 21 .…”

Section: Patientsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Kobayashi

Mukaida

Migita

et al. 2011

Anaesth Intensive Care

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“…However, the muscle contracture test can be confounded by many factors, including gender and size of muscle preparations [Robinson et al., ]. In contrast, heterologous expression systems of RYR1 in HEK293 cells [Tong et al., ; Wehner et al., ; Monnier et al., ; Migita et al., ] is well‐suited to evaluate effects of RYR1 mutations themselves on channel function because this system is free from background of individual patients. In the course of this and previous works [Murayama, ], we noticed the following important differences in Ca 2+ homeostasis between HEK293 cell systems and skeletal muscles or myotubes.…”

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel

et al. 2016

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Type 1 ryanodine receptor (RYR1) is a Ca release channel in the sarcoplasmic reticulum of skeletal muscle and is mutated in some muscle diseases, including malignant hyperthermia (MH) and central core disease (CCD). Over 200 mutations associated with these diseases have been identified, and most mutations accelerate Ca -induced Ca release (CICR), resulting in abnormal Ca homeostasis in skeletal muscle. However, it remains largely unknown how specific mutations cause different phenotypes. In this study, we investigated the CICR activity of 14 mutations at 10 different positions in the central region of RYR1 (10 MH and four MH/CCD mutations) using a heterologous expression system in HEK293 cells. In live-cell Ca imaging, the mutant channels exhibited an enhanced sensitivity to caffeine, a reduced endoplasmic reticulum Ca content, and an increased resting cytoplasmic Ca level. The three parameters for CICR (Ca sensitivity for activation, Ca sensitivity for inactivation, and attainable maximum activity, i.e., gain) were obtained by [ H]ryanodine binding and fitting analysis. The mutant channels showed increased gain and Ca sensitivity for activation in a site-specific manner. Genotype-phenotype correlations were explained well by the near-atomic structure of RYR1. Our data suggest that divergent CICR activity may cause various disease phenotypes by specific mutations.

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“…Over 300 RyR mutations have been associated with disorders (54), including the RyR myopathies malignant hyperthermia (69,72), central core disease (63), multiminicore disease (25), atypical periodic paralyses (125), catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia type 2 (64,87,120). The RyR has also been indirectly linked to acquired pathologies such as heart failure (95) and over-exercise muscle fatigue (4).…”

Section: Ryr-associated Pathologiesmentioning

confidence: 99%

Ryanodine Receptor

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47

Abstract: We demonstrated that the transfected RYR1 mutant was more sensitive to caffeine and 4CmC than wildtype RYR1. These findings suggest that the p.R2508C mutation may be pathogenetic for susceptibility to MH.

Cited by 13 publications

References 17 publications

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Genotype-Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel

Ryanodine Receptor

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