title: The role of CACNA1S in predisposition to malignant hyperthermia.
abstract: BACKGROUND
  Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the alpha1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK.
  
  
  METHODS
  We investigate the CACNA1S locus in detail in 50 independent MH patients, the largest study to date, to identify novel variants that may predispose to disease and also to characterise the haplotype structure across CACNA1S.
  
  
  RESULTS
  We present CACNA1S cDNA sequencing data from 50 MH patients in whom RYR1 mutations have been excluded, and subsequent mutation screening analysis. Furthermore we present haplotype analysis of unphased CACNA1S SNPs to (1) assess CACNA1S haplotype frequency differences between susceptible MH cases and a European control group and (2) analyse population-based association via clustering of CACNA1S haplotypes based on disease risk.
  
  
  CONCLUSIONS
  The study identified a single potentially pathogenic change in CACNA1S (p.Arg174Trp), and highlights that the haplotype structure across CACNA1S is diverse, with a high degree of variability.
authors.affiliation: MH Investigation Unit, Academic Unit of Anaesthesia, St James's University Hospital, Leeds, LS9 7TF, UK. danielle.carpenter@nottingham.ac.uk
authors.forename: Danielle
authors.initials: D
authors.lastname: Carpenter
authors.forename: Christopher
authors.initials: C
authors.lastname: Ringrose
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leo
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Robinson
authors.forename: P Jane
authors.initials: PJ
authors.lastname: Halsall
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Shaw
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002110:Caffeine / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006221:Halothane / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000503:physiopathology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002110:Caffeine; D006221:Halothane