title: Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.
abstract: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.
authors.affiliation: Department of Biochemistry, University College Cork, Cork, Ireland.
authors.forename: B M
authors.initials: BM
authors.lastname: Manning
authors.forename: K A
authors.initials: KA
authors.lastname: Quane
authors.forename: H
authors.initials: H
authors.lastname: Ording
authors.forename: A
authors.initials: A
authors.lastname: Urwyler
authors.forename: V
authors.initials: V
authors.lastname: Tegazzin
authors.forename: M
authors.initials: M
authors.lastname: Lehane
authors.forename: J
authors.initials: J
authors.lastname: O'Halloran
authors.forename: E
authors.initials: E
authors.lastname: Hartung
authors.forename: L M
authors.initials: LM
authors.lastname: Giblin
authors.forename: P J
authors.initials: PJ
authors.lastname: Lynch
authors.forename: P
authors.initials: P
authors.lastname: Vaughan
authors.forename: K
authors.initials: K
authors.lastname: Censier
authors.forename: D
authors.initials: D
authors.lastname: Bendixen
authors.forename: G
authors.initials: G
authors.lastname: Comi
authors.forename: L
authors.initials: L
authors.lastname: Heytens
authors.forename: K
authors.initials: K
authors.lastname: Monsieurs
authors.forename: T
authors.initials: T
authors.lastname: Fagerlund
authors.forename: W
authors.initials: W
authors.lastname: Wolz
authors.forename: J J
authors.initials: JJ
authors.lastname: Heffron
authors.forename: C R
authors.initials: CR
authors.lastname: Muller
authors.forename: T V
authors.initials: TV
authors.lastname: McCarthy
mesh_terms: D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel