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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e3182a273ea
Pediatric Anesthesiology: Research Report

Functional Characterization of 2 Known Ryanodine Receptor Mutations Causing Malignant Hyperthermia

Schiemann, Anja H. PhD*; Paul, Neeti*; Parker, Remai*; Pollock, Neil MB ChB, FRCA, FANZCA, MD; Bulger, Terasa F. MB ChB, FRCA, FANZCA; Stowell, Kathryn M. PhD*

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BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: We propose that R2355W is confirmed as being an MH-causative mutation and suggest that V2354M is a RYR1 mutation likely to cause MH.

© 2014 International Anesthesia Research Society

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