Molecular screening for specific causative mutations in the South African malignant hyperthermia population

Abstract

Malignant hyperthermia (MH) is an autosomal dominant, pharmacogenetic disorder. MH susceptible (MHS) patients appear clinically normal, but may present with a hypermetabolic crisis and muscle contracture when exposed to triggering substances which elicit excessive release of calcium ions from the sarcoplasmic reticulum. The underlying cause of MH has emerged as biochemical abnormalities that occur in skeletal muscle. Presymptomatic diagnosis of MH susceptibility is currently made via the in vitro contracture test. The phenotypically similar porcine MH model led to the identification of the chromosomal region bearing the underlying defect. The first human MHS locus, MHS-1, has been mapped to chromosome 19q13. MH is mainly due to mutations in the skeletal muscle ryanodine receptor gene (RYRI). To date the RYRI gene has been associated with an MH phenotype in approximately 50% of MH families. However, the disorder is genetically heterogeneous, as six other loci have to date been associated with MHS. The aim of the molecular investigation presented here was to determine if 24 recently reported causative mutations in the RYRI gene are present in any of the 45 South African MHS probands investigated. Furthermore, eight mutations of the RYRI gene and the Arg1086His mutation of the CACNAIS that have already been analysed in previous phases of the research programme were investigated. One alteration, Thr482611e was detected for the first time in a single South African MH family, contributing to the description of the aetiology of MHS in South Africa. None of the remaining alterations were detected in any South African MH probands analysed. The absence of the majority of reported mutations in all probands included in this study could indicate that the mutations either represent family-specific alterations or could be attributed to the fact that these mutations do not play a role in MHS in the South African population.