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Updated: Jul 10, 2025
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Functional characterization of RYR1 variants identified in malignant hyperthermia susceptible individuals
Yuko Noda1, Hirotsugu Miyoshi2, Sofia Benucci3
1Departments of Biomedicine and Neurology, Basel University Hospital, Hebelstrasse 20, Basel 4031, Switzerland; Department of Anesthesiology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku Hiroshima, 734-8551, Japan.
Abstract:
Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.
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