title: Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families.
abstract: BACKGROUND
  Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown.
  
  
  METHODS
  De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes.
  
  
  RESULTS
  Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM).
  
  
  CONCLUSIONS
  The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Groom
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Muldoon
authors.forename: Zhen Zhi
authors.initials: ZZ
authors.lastname: Tang
authors.forename: Barbara W
authors.initials: BW
authors.lastname: Brandom
authors.forename: Munkhuu
authors.initials: M
authors.lastname: Bayarsaikhan
authors.forename: Saiid
authors.initials: S
authors.lastname: Bina
authors.forename: Hee-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Xing
authors.initials: X
authors.lastname: Qiu
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
mesh_terms: D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium