Functional characterization of 2 known ryanodine receptor mutations causing malignant hyperthermia.

Anesthesia and Analgesia
A H SchiemannK Stowell

Abstract

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder. More than 300 variants in the ryanodine receptor 1 (RYR1) have been associated with MH; however, only 31 have been identified as causative. To confirm a mutation in RYR1 as being causative for MH, segregation of the potential mutation in at least 2 unrelated families with MH susceptibility must be demonstrated and functional assays must show abnormal calcium release compared with wild-type RYR1. We used "Hot-spot" DNA screening to identify mutations in RYR1 in 3 New Zealand families. B-lymphoblastoid cells were used to compare the amount of calcium released on stimulation with 4-chloro-m-cresol between wild-type RYR1 cells and cells carrying the new variants in RYR1. We identified a known RYR1 mutation (R2355W) in 2 families and another more recently identified (V2354M) mutation in another family. Both mutations segregated with MH susceptibility in the respective families. Cell lines carrying a mutation in RYR1 showed increased sensitivity to 4-chloro-m-cresol. We propose that R2355W is confirmed as being an MH-causative mutation and suggest that V2354M is a RYR1 mutation likely to cause MH.

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Citations

Aug 5, 2015·Orphanet Journal of Rare Diseases·Henry RosenbergKathryn Stowell
Dec 29, 2015·Pharmacogenetics and Genomics·Maria L AlvarellosTeri E Klein
Aug 20, 2021·The Journal of Physiology·Alla F Fomina
Apr 14, 2017·British Journal of Anaesthesia·A MerrittP M Hopkins

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