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17.01.2018 | Original Article

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

verfasst von: Takashi Kondo, Toshimichi Yasuda, Keiko Mukaida, Sachiko Otsuki, Rieko Kanzaki, Hirotsugu Miyoshi, Hiroshi Hamada, Ichizo Nishino, Masashi Kawamoto

Erschienen in: Journal of Anesthesia | Ausgabe 2/2018

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Abstract

Purpose

The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.

Methods

DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca²⁺ measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC₅₀) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose–response curves. The EC₅₀ was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met.

Results

Dose–response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons).

Conclusions

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

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Titel: Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia
verfasst von: Takashi Kondo
Toshimichi Yasuda
Keiko Mukaida
Sachiko Otsuki
Rieko Kanzaki
Hirotsugu Miyoshi
Hiroshi Hamada
Ichizo Nishino
Masashi Kawamoto
Publikationsdatum: 17.01.2018
Verlag: Springer Japan
Erschienen in: Journal of Anesthesia / Ausgabe 2/2018
Print ISSN: 0913-8668
Elektronische ISSN: 1438-8359
DOI: https://doi.org/10.1007/s00540-018-2451-6

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

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

Purpose

Methods

Results

Conclusions

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