title: Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.
abstract: Malignant hyperthermia (MH) is an anesthetic-drug-induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release-channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.
authors.affiliation: Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sambuughin
authors.forename: S
authors.initials: S
authors.lastname: McWilliams
authors.forename: A
authors.initials: A
authors.lastname: de Bantel
authors.forename: K
authors.initials: K
authors.lastname: Sivakumar
authors.forename: T E
authors.initials: TE
authors.lastname: Nelson
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000503:physiopathology*; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000503:physiopathology*; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel