title: Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia.
abstract: Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalation anaesthetics and depolarizing neuromuscular blocking agents. To date, eight mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. We have screened the RYR1 gene in affected individuals for novel MHS mutations by single stranded conformational polymorphism (SSCP) analysis and have identified a G to T transition mutation which results in the replacement of a conserved arginine (Arg) at position 614 with a leucine (Leu). The Arg614Leu mutation was present in three unrelated MHS individuals of 151 investigated. The mutation was not detected in 148 normal chromosomes and segregated precisely with MHS in family members from one of the probands where DNA was available for analysis. This mutation occurs at the same position as the previously identified Arg to Cys mutation reported in all cases of porcine MH and in approximately 5% of human MH. A comparison of the phenotypes of the Arg614Leu and Arg614Cys probands is presented.
authors.affiliation: Department of Biochemistry, University College, Cork, Ireland.
authors.forename: K A
authors.initials: KA
authors.lastname: Quane
authors.forename: H
authors.initials: H
authors.lastname: Ording
authors.forename: K E
authors.initials: KE
authors.lastname: Keating
authors.forename: B M
authors.initials: BM
authors.lastname: Manning
authors.forename: R
authors.initials: R
authors.lastname: Heine
authors.forename: D
authors.initials: D
authors.lastname: Bendixen
authors.forename: K
authors.initials: K
authors.lastname: Berg
authors.forename: R
authors.initials: R
authors.lastname: Krivosic-Horber
authors.forename: F
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: T
authors.initials: T
authors.lastname: Fagerlund
authors.forename: T V
authors.initials: TV
authors.lastname: McCarthy
mesh_terms: D000595:Amino Acid Sequence; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000235:genetics; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics*; D013045:Species Specificity
chemical_list: D018685:Anesthetics, Inhalation; D019837:Ryanodine Receptor Calcium Release Channel; D001120:Arginine; D007930:Leucine