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- Title
Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia.
- Authors
Kondo, Takashi; Yasuda, Toshimichi; Mukaida, Keiko; Otsuki, Sachiko; Kanzaki, Rieko; Miyoshi, Hirotsugu; Hamada, Hiroshi; Nishino, Ichizo; Kawamoto, Masashi
- 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-<italic>m</italic>-cresol (4C<italic>m</italic>C), 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 4C<italic>m</italic>C were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4C<italic>m</italic>C were significantly lower in both myotubes and HEK-293 cells compared to controls (<italic>P</italic> < 0.001 for all comparisons).Conclusions: Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4C<italic>m</italic>C. We conclude that the genetic variant was associated with MH susceptibility.
- Subjects
MALIGNANT hyperthermia; MUSCLE weakness; DNA analysis; MICROBIAL virulence; FUNCTIONAL analysis; GENETICS
- Publication
Journal of Anesthesia, 2018, Vol 32, Issue 2, p174
- ISSN
0913-8668
- Publication type
Article
- DOI
10.1007/s00540-018-2451-6