Molecular screening of the Skeletal Muscle Ryanodine Receptor (RYR1) gene for mutations associated with malignant hyperthermia susceptibility

Abstract

Malignant hyperthermia (MH) is a pharmaco-induced syndrome, characterised by muscle contractures, hypermetabolism and elevated body temperatures. Clinically inconspicuous, this autosomal dominant genetic predisposition is a response to individual exposure to inhalational anaesthetics or depolarising muscle relaxants. If not treated immediately, MH results in severe tissue damage, organ failure and death. Although treatment has led to a significant decline in mortality associated with MH, it still remains the most common cause of death from general anaesthetic. Unusual anaesthetic reactions are estimated at 1 in 15 ,000 children and 1 in 40 ,000 adults. Various mutations in the skeletal muscle ryanodine receptor (RYR1) gene located on chromosome 19q13.1, and encoding the calcium release channel of skeletal muscle, can account for susceptibility to MH. More than thirty different mutations have been reported within the RYR1 gene, although on ly seventeen have been demonstrated to be causative. A selected group of fifty five individuals were investigated in this mutation screening study. The following nine reported mutations were analysed: Arg163Cys, Gly341 Arg, lle403Met, Val2168Met, Thr2206Met, Gly2433Arg, Arg2434His, Arg2458Cys and Arg2458His. One mutation, Val2168Met, was observed in this group of MH individuals. The detection of this transition within the South African population, thus, has significant implications not only in the molecular analysis of MH but also in the identification of the MH genotype responsible for this disorder in South Africa. None of the remaining eight mutations investigated were detected in the group of individuals included in this study. These DNA alterations, therefore, do not contribute to the MH phenotype of any of these individuals. If the individuals included in this investigation are a true representation of the South African and North American populations, it may be concluded that the aforementioned mutations are absent from these populations. These mutations are, therefore, still considered to be population or even family specific.