Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia

Kondo, Takashi; Yasuda, Tomoo; Mukaida, Keiko; Otsuki, Sachiko; Kanzaki, Rieko; Miyoshi, Hirotsugu; Hamada, Hiroshi; Nishino, Ichizo; Kawamoto, Masashi

doi:10.1007/s00540-018-2451-6

Cited by 8 publications

(3 citation statements)

References 29 publications

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“…In this study, G1530T in CACNA1S was suggested to be pathogenic by 6 prediction software, and C4615T was suggested to be pathogenic by 5 prediction software. (Table 3) (3,14,15). Recent evidence has also con rmed the foresight of requiring functional analysis of missense variants before their adoption for diagnostic use (14).…”

Section: Resultsmentioning

confidence: 97%

Identification of Gene Variants Related to Malignant Hyperthermia in Han Chinese People by Next-Generation Sequencing.

Zhang¹,

Fu²,

Li³

et al. 2020

Preprint

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Background: Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by anesthesia. In recent years, next generation sequencing(NGS) technology, targeted sequencing approaches have been used to identify regions related to MH and can not only detect known MH variant sites but also allow the exploration of novel MH-related variants.Methods: Twenty-four volunteer’s blood samples were collected, genomic DNA was then extracted, target regions were amplified, and through targeted sequencing of these target regions, both known and novel variants were identified, and analysis of these variants identified some that may damage protein function. Online prediction tools were also used to determine the possibility of variants that may cause MH.Results: We performed next-generation sequencing of 53 positions on 4 genes, in which 36 variants of the RYR1 gene were found. Three of these caused a change in the amino acid sequence. Additionally, 11 variants of the CACNA1S gene were found, of which 3 led to amino acid sequence changes. Five variants of the JSRP1 gene were found, and four variants caused the amino acid sequence to change.Conclusions: In healthy volunteers, variants in RYR1 and CACNA1S were more common, and variants in JSRP1 more commonly had amino acid sequence changes. Whether a variant is pathogenic can be predicted using a prediction website, but the sensitivity and specificity still need to be improved.

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Section: Resultsmentioning

confidence: 97%

Identification of Gene Variants Related to Malignant Hyperthermia in Han Chinese People by Next-Generation Sequencing.

Zhang¹,

Fu²,

Li³

et al. 2020

Preprint

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“…1 T84M and Q155K were functionally analysed in a previous study and have been suggested to contribute to MH crisis. 16,17 Using a modified version of the American College of Medical Genetics and Genomics guidelines, 18 the T84M and Q155K variants can be classified as uncertain significance and likely pathogenic, respectively.…”

Section: Discussionmentioning

confidence: 99%

The effects of dantrolene in the presence or absence of ryanodine receptor type 1 variants in individuals predisposed to malignant hyperthermia

Noda

Mukaida

Miyoshi

et al. 2022

Anaesth Intensive Care

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Dantrolene is currently the only drug known to specifically treat malignant hyperthermia (MH) crises. Although dantrolene attenuates Ca2+ disorders by acting mainly on the ryanodine receptor type 1 (RYR1), some patients who manifest MH without RYR1 variants have also been successfully treated with dantrolene. Thus, dantrolene appears to have an inhibitory effect on patients with and without RYR1 variants. This study aimed to investigate whether the effects of dantrolene differed depending on the presence or absence of RYR1 variants using muscle cells from MH-predisposed individuals. The study participants were individuals diagnosed with MH predisposition by the Ca2+-induced Ca2+ release rate test. They were genetically tested and divided into two groups: with and without RYR1 variants. We investigated whether these two groups showed differences in the changes in the half-maximal effective concentration (EC50) for caffeine and the resting intracellular Ca2+ concentration ([Ca2+]i) before and after dantrolene administration. Dantrolene administration significantly increased the EC50 ( P < 0.0001) and decreased the resting [Ca2+]i ( P < 0.0001). The inhibitory effects of dantrolene and the presence of RYR1 variants showed no statistically significant interactions related to the EC50 ( P = 0.59) and resting [Ca2+]i ( P = 0.21). In conclusion, the presence or absence of RYR1 variants does not appear to influence the effect of dantrolene.

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“…MH can be diagnosed clinically, which evaluates clinical presentation and laboratory findings, or MH can be diagnosed by in vitro testing, which examines the presence or absence of MH susceptibility, including a muscle biopsy and genetic analysis [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events

Toyota

Kondo

Shorin

et al. 2023

BioMed Research International

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Purpose. Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further. Methods. Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis. Results. 128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene ( P = 0.047 ). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, P < 0.001 ), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, P < 0.001 ). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature ( P < 0.001 ). The multivariable analysis also showed that the patient’s temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis. Conclusions. Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.

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Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia

Abstract: Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.

Cited by 8 publications

References 29 publications

Identification of Gene Variants Related to Malignant Hyperthermia in Han Chinese People by Next-Generation Sequencing.

Identification of Gene Variants Related to Malignant Hyperthermia in Han Chinese People by Next-Generation Sequencing.

The effects of dantrolene in the presence or absence of ryanodine receptor type 1 variants in individuals predisposed to malignant hyperthermia

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events

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