Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder (Deufel et aI., 1992). It is potentially fatal and one of the leading causes of death due to anaesthesia. An MH episode is triggered when MH susceptible individuals are exposed to certain inhalation anaesthetic agents and depolarising skeletal muscle relaxants (Maclennan, 1992). To date, twenty-three mutations have been reported in the skeletal muscle ryanodine receptor gene (RYR1), located on chromosome 19q13.1, and twenty-two of these mutations have been associated with MH (Brandt et aI., 1999). The 1403M mutation has only been associated with central core disease (CCD). CCD and MH are phenotypically distinct allelic variants as mutations in the same gene are responsible for both these disorders (Quane et al., 1993). Seventeen MH families, four South African and thirteen North American families, were included in this study. DNA from selected MH individuals were screened for nine of the reported mutations (Cys35Arg, Arg163Cys, Gly248Arg, Gly341Arg, lIe403Met, Tyr522Ser, Arg614Cys, Gly2435Arg and Arg2436His). The interaction between polymorph isms and mutations, which might modify or contribute to the MH phenotype, is currently still unknown. For this reason the DNA from selected individuals were screened for the presence of all of the nine mutations investigated in this study. Two mutations, Arg614Cys and Gly2435Arg, were observed in the group of MH families included in this study. The Arg614Cys mutation was identified in a large South African MH family (MH105). A total of 39 individuals of South African family MH105 were subsequently screened for the presence of this mutation. Twelve individuals, three of whom have not been tested via the in vitro contracture test (IVCT), were positive for the mutation. Two individuals from this family displayed phenotype-genotype discordance. The Gly2435Arg mutation was identified in a North American MH family (US2). This small family of five individuals included three individuals diagnosed via the North American IVCT protocol. The three phenotyped individuals included two MH positive and one MH negative individual. The Gly2435Arg mutation segregated with the MH phenotype observed in this North American family. This is the first report of the Gly2435Arg mutation in the North American MH population. The identification of the Arg614Cys and Gly2435Arg mutations contributed towards establishing a molecular diagnostic service for individuals within these particular MH families. None of the other seven mutations investigated were detected in the group of families included in this study. The DNA alterations are therefore not present as polymorphisms in these families, and can thus not contribute to the MH phenotype segregating in any of the families. If the families investigated in this study are truly representative of the South African and North American populations it is possible that these seven mutations are absent in these two populations. These mutations might, therefore, be population specific or even family specific. / Dissertation (MSc)--University of Pretoria, 2010. / Genetics / unrestricted