title: Functional characterization of 2 known ryanodine receptor mutations causing malignant hyperthermia.
abstract: 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.
authors.affiliation: From the Institute of Fundamental Sciences, Massey University; and Department of Anaesthesia and Intensive Care, MidCentral Health, Palmerston North Hospital, Palmerston North, New Zealand.
authors.forename: Anja H
authors.initials: AH
authors.lastname: Schiemann
authors.forename: Neeti
authors.initials: N
authors.lastname: Paul
authors.forename: Remai
authors.initials: R
authors.lastname: Parker
authors.forename: Neil
authors.initials: N
authors.lastname: Pollock
authors.forename: Terasa F
authors.initials: TF
authors.lastname: Bulger
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Stowell
mesh_terms: D000293:Adolescent; D000328:Adult; D000758:Anesthesia / Q000009:adverse effects; D001402:B-Lymphocytes / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002648:Child; D019295:Computational Biology; D003408:Cresols / Q000494:pharmacology; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D003408:Cresols; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D002118:Calcium