title: Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population.
abstract: OBJECTIVE
  Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population.
  
  
  METHODS
  In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families.
  
  
  RESULTS
  Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations.
  
  
  CONCLUSIONS
  The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing.
authors: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, Toronto, ON, Canada.
authors: Natasha
authors: N
authors: Kraeva
authors: Sheila
authors: S
authors: Riazi
authors: Julian
authors: J
authors: Loke
authors: Wanda
authors: W
authors: Frodis
authors: Mary Lou
authors: ML
authors: Crossan
authors: Kevin
authors: K
authors: Nolan
authors: Alexander
authors: A
authors: Kraev
authors: David H
authors: DH
authors: Maclennan
mesh_terms: D000595:Amino Acid Sequence; D056726:Genetic Association Studies; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel