Screening of the RYR1 gene in malignant hyperthermia probands from South Africa indicates towards a novel epigenetic eatiology in this population

Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2008. Malignant hyperthermia (MH) is an autosomal dominant, potentially lethal pharmacogenetic disorder of skeletal muscle, which is elicited by exposure to volatile anaesthetics and depolarising muscle relaxants. Susceptible individuals appear clinically normal, but may present with a hypermetabolic crisis and muscle contracture when exposed to triggering substances that elicit excessive release of calcium ions from the sarcoplasmic reticulum. Diagnosis of MH susceptibility is currently made via the in vitro contracture test. Genetically, in more than 50% of the affected families, MH occurs due to alterations in the skeletal muscle ryanodine receptor gene (RYR1) on chromosome 19q13.1. However, the disorder is genetically heterogeneous, as six other loci have to date been associated with MH susceptibility (MHS). Thus far, molecular tests have focused on three mutation hotspots of the RYR1 gene, which refer to regions that are more frequently mutated. Screening the entire RYR1 has led to a higher detection rate in a variety of populations. In this study the entire coding region of the RYR1 gene was screened via sequencing for novel or reported alterations for the first time in 15 South African probands. Eight different RYR1 alterations were observed in seven MHS South African probands, six of which were previously reported and two of which were novel. Compound heterozygous alterations and alterations outside the mutation hotspots were detected. Screening of the entire coding region of the RYR1 gene is crucial for genetic investigations into MHS. It was postulated that MH in the South African population is due to multifactorial inheritance in which a network of several genetic, environmental and epigenetic factors interact and cumulatively result in the development of the MH phenotype. Data generated in this study highlight the complexity of this disorder, further supporting a novel epigenetic aetiology for MH in the South African population. Doctoral