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.

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

“…MH susceptibility and CCD are allelic conditions stemming from predominantly dominant mutations in the type 1 ryanodine receptor (RYR1) gene. RYR1 encodes the skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1) (12)(13)(14), and more than 178 mutations have been identified throughout the RYR1 gene to date, most of them missense mutations, with a few being deletions and splicing site mutations (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A few rare mutations conferring MH susceptibility have been associated with mutations in CaV1.1, the major subunit of the sarcolemmal slow voltage-gated Ca 2ϩ channel (CACNA1S, dihydropyridine receptor) (25,26).…”

Central core disease

“…A few small deletions [59,60,64] and cryptic splicing site mutations [63,65] have been documented. The majority of RYR1 mutations associated with MHS or CCD described to date were dominant mutations; homozygosity or heterozygosity for RYR1 mutations has been previously documented in association with MHS [66,67] and have been recently reported in a severe form of CCD presenting with a foetal akinesia syndrome [15] and few mild cases [16].…”

Identification of two αRYR alleles and characterization of αRYR transcript variants in turkey skeletal muscle

“…More than 20 missense mutations and one amino acid deletion in RYR1 have been associated with human MH (Jurkat-Rott et al, 2000;Sambuughin et al, 2001). MH-associated mutations in RYR1 mainly cluster in two regions: mutation hot spot 1 (amino acid residues 35 -615) and hot spot 2 (residues 2162 -2458).…”