Detection of a Novel Ryanodine Receptor Subtype 1 Mutation (R328W) in a Malignant Hyperthermia Family by Sequencing of a Leukocyte Transcript

Loke, Julian; Kraev, Natasha; Sharma, Parveen; Du, Guo-Guang; Patel, Leena; Kraev, Alexander; MacLennan, David H.

doi:10.1097/00000542-200308000-00011

Cited by 17 publications

(3 citation statements)

References 28 publications

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“…In the present study, the EC 50 values for the three RYR1 activators tested in cultured myotubes from the accelerated group were two-fold lower than those of the nonaccelerated group. These results are similar to those previously obtained using the same experimental system (human cultured myotubes expressing MH mutations [22][23][24][25] ) as well as other experimental models (human embryonic kidney cells 26 or dyspedic myotubes 4 transfected with RyR1 cDNAs possessing some MH mutations, and lymphoblastoid cells 27,28 ).…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Kobayashi

Mukaida

Migita

et al. 2011

Anaesth Intensive Care

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“…The cohort of 133 unrelated MHS patients and 46 patients at risk for MHS was screened for 25 RYR1 mutations, 18 known causative mutations [Tong et al, 1997;Sambuughin et al, 2001b;Urwyler et al, 2002;Oyamada et al, 2002;Loke et al, 2003], and seven mutations tested in this study because of their recurrence. As indicated in Table 1, a causative mutation was identified in 58 MHS index cases and eight of the at-risk patients.…”

Section: Mutation Screening For Causative Mutationsmentioning

confidence: 99%

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility

et al. 2005

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Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.

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“…These variants were only reported in cohort studies without detailed case or family descriptions. 9e11 We found only one small MHS family with the p.Arg328Trp variant 12 and two siblings with the p.Ile403Met variant associated with core myopathy without MHS diagnosis. 13 Taken together, our results question the specificity of p.Arg328Trp, p.Ile403Met, p.Arg530His, and p.Arg533His variants for MHS.…”

mentioning

confidence: 87%

Estimating prevalence of malignant hyperthermia susceptibility through population genomics data

Mungunsukh¹,

Deuster²,

Muldoon³

et al. 2019

British Journal of Anaesthesia

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Detection of a Novel Ryanodine Receptor Subtype 1 Mutation (R328W) in a Malignant Hyperthermia Family by Sequencing of a Leukocyte Transcript

Abstract: The feasibility of using complete RYR1 transcripts from leukocytes for sequence analysis offers an efficient and noninvasive method for scanning RYR1 for novel mutations.

Cited by 17 publications

References 28 publications

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility

Estimating prevalence of malignant hyperthermia susceptibility through population genomics data

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