title: Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.
abstract: BACKGROUND
  Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis.
  
  
  METHODS
  RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner. The α-1 subunit of the dihydropyridine receptor gene (CACNA1S) was screened for 4 variants in subjects in whom no abnormality was found in ≥ 100 exons of RYR1.
  
  
  RESULTS
  Ten known causative MH mutations were found in 26 subjects. Variants of uncertain significance in RYR1 were found in 36 subjects, 16 of which are novel. Novel variants in both RYR1 and CACNA1S were found in the 1 subject who died of MH. Two RYR1 variants were found in 4 subjects. Variants of uncertain significance were found outside and inside the hotspots of RYR1. Maximal contractures in the caffeine-halothane contracture test were greater in those who had a known MH mutation or variant of uncertain significance in RYR1 than in those who did not.
  
  
  CONCLUSIONS
  The identification of novel RYR1 variants and previously observed RYR1 variants of uncertain significance in independent MHS families is necessary for demonstrating the significance of these variants for MH susceptibility and supports the need for functional studies of these variants. Continued reporting of the clinical phenotypes of MH is necessary for interpretation of genetic findings, especially because the pathogenicity of most of these genetic variants associated with MHS remains to be elucidated.
authors.affiliation: From the Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Department of Anesthesiology, Northwestern University, Chicago, Illinois; Children's Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and Departments of Pediatrics, Neurology, Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Barbara W
authors.initials: BW
authors.lastname: Brandom
authors.forename: Saiid
authors.initials: S
authors.lastname: Bina
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Wong
authors.forename: Tarina
authors.initials: T
authors.lastname: Wallace
authors.forename: Mihaela
authors.initials: M
authors.lastname: Visoiu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Isackson
authors.forename: Georgirene D
authors.initials: GD
authors.lastname: Vladutiu
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Muldoon
mesh_terms: D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005091:Exons / Q000235:genetics; D014644:Genetic Variation; D006221:Halothane / Q000009:adverse effects / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D008305:Malignant Hyperthermia / Q000453:epidemiology / Q000235:genetics*; D009119:Muscle Contraction / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D014481:United States / Q000453:epidemiology
chemical_list: D018685:Anesthetics, Inhalation; C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA; D006221:Halothane
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