title: CASQ1 gene is an unlikely candidate for malignant hyperthermia susceptibility in the North American population.
abstract: Malignant hyperthermia (MH, MIM# 145600) is a complex pharmacogenetic disorder that is manifested in predisposed individuals as a potentially lethal reaction to volatile anesthetics and depolarizing muscle relaxants. Studies of CASQ1-null mice have shown that CASQ1, encoding calsequestrin 1, the major Ca2+ binding protein in the lumen of the sarcoplasmic reticulum, is a candidate gene for MH in mice. The aim of this study was to establish whether the CASQ1 gene is associated with MH in the North American population.
  
  
  
  The entire coding region of CASQ1 in 75 unrelated patients diagnosed by caffeine-halothane contracture test as MH susceptible (MHS) was analyzed by DNA sequencing. Subsequently, three groups of unrelated individuals (130 MHS, 100 MH negative, and 192 normal controls) were genotyped for a variant that was identified by sequencing. Levels of CASQ1 expression in the muscle from unrelated MHS and MH negative individuals were estimated by Western blotting.
  
  
  
  Screening of the entire coding sequence of the CASQ1 gene in 75 MHS patients revealed a single variant c.260T > C (p.Met87Thr) in exon 1. This variant is unlikely to be pathogenic, because its allele frequency in the MHS group was not significantly different from that of controls. There was also no difference in calsequestrin 1 protein levels between muscle samples from MHS and controls, including those carrying the p.Met87Thr variant.
  
  
  
  This study revealed a low level of protein coding sequence variability within the human CASQ1 gene, indicating that CASQ1 is not a major MHS locus in the North American population.
authors: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Natalia
authors: N
authors: Kraeva
authors: Elena
authors: E
authors: Zvaritch
authors: Wanda
authors: W
authors: Frodis
authors: Olga
authors: O
authors: Sizova
authors: Alexander
authors: A
authors: Kraev
authors: David H
authors: DH
authors: MacLennan
authors: Sheila
authors: S
authors: Riazi
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002155:Calsequestrin; D019295:Computational Biology; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008305:Malignant Hyperthermia / Q000453:epidemiology* / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D009656:North America / Q000453:epidemiology; D012313:RNA / Q000235:genetics; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D044465:White People
chemical_list: C412223:CACNA1S protein, human; C503129:CASQ1 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D024101:Mitochondrial Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D012313:RNA; D004247:DNA