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- Title
Functional analysis of newly identified RYR1 variants in patients susceptible to malignant hyperthermia.
- Authors
Noda, Yuko; Yasuda, Toshimichi; Kanzaki, Rieko; Miyoshi, Hirotsugu; Mukaida, Keiko; Kamiya, Satoshi; Morio, Atsushi; Hamada, Hiroshi; Kawamoto, Masashi; Tsutsumi, Yasuo M.
- Abstract
Purpose: This study aimed to evaluate whether the three ryanodine receptor type 1 (RYR1) variants (p.Ser2345Thr, p.Ser2345Arg, and p.Lys3367Arg) which we identified in Japanese malignant hyperthermia (MH) patients with a clinical grading scale rank of 6 were causative for MH. Methods: We prepared human embryonic kidney (HEK)-293 cells transfected with wild-type RYR1 or one of the RYR1 variants, along with myotubes cultured from muscle pieces. Calcium kinetics were examined by calculating the 340/380-nm ratio under various caffeine and 4-chloro-m-cresol (4CmC) concentrations with the ratiometric dye Fura-2 AM. Half-maximal effective concentration (EC50) values were calculated from dose–response curves. Statistical analysis was based on one-way analysis of variance with a Dunnett's multiple comparison test, using a P value < 0.05 as evidence of statistical significance. Results: In functional analysis using HEK-293 cells, we found significant reductions in the EC50 of p.Ser2345Thr and p.Ser2345Arg in comparison with wild-type RYR1 (P < 0.001), while the EC50 of p.Lys3367Arg was not significantly different (P = 0.062 for caffeine and P > 0.999 for 4CmC). On the other hand, functional analysis using myotubes showed significant differences in the EC50 values for all variants (P < 0.001 for all comparisons). Conclusions: p.Ser2345Thr and p.Ser2345Arg appear capable of causing a calcium metabolism disorder that leads to the onset of MH, and p.Ser2345Arg can be considered as a diagnostic mutation, because it meets the European Malignant Hyperthermia Group criteria. However, patients with p.Lys3367Arg might have mutations in genes other than RYR1 that are capable of causing MH.
- Subjects
MALIGNANT hyperthermia; FUNCTIONAL analysis; RYANODINE receptors; ONE-way analysis of variance; CALCIUM metabolism; GENETIC mutation
- Publication
Journal of Anesthesia, 2020, Vol 34, Issue 5, p658
- ISSN
0913-8668
- Publication type
Article
- DOI
10.1007/s00540-020-02803-w