|dc.description.abstract||Mitochondria are the "power houses" of each cell, sustaining the cell's energy demands by providing energy in the form of adenosine triphosphate (ATP). ATP is produced inside the mitochondria during cellular oxidative phosphorylation (OXPHOS). During this process, numerous reducing agents work together to finally produce ATP by the last enzyme of the OXPHOS system. Oxygen acts as the final electron acceptor in the electron transport chain (ETC), which is composed by the first four enzymes of the OXPHOS system.
The OXPHOS system is an electrochemical pump situated in the mitochondrial inner membrane. It contains subunits that are encoded by nuclear and mitochondrial DNA respectively. Mitochondrial DNA (mtDNA) encodes 13 peptides (part of the OXPHOS system), 22 transfer RNAs and 2 ribosomal RNAs. Disorders of this system can arise from mutations in either mitochondrial or nuclear DNA and are responsible for the most prevalent inborn (inherited) errors of metabolism in children. Various disorders with ranging severity have been linked to mitochondrial disorders that affect the energy production of the cell. This is especially evident when mutations in mtDNA occur. Therefore, the integrity of mtDNA is of utmost importance to primarily ensure the sufficient production of ATP within each cell.
Mitochondrial DNA polymerase gamma (mtDNA POLG or POLG) is the only nuclear encoded DNA polymerase involved in the replication of mtDNA. It has recently been shown that there is a high probability of POLG1 gene mutations (~25%) in mitochondrial disorders.
Very little is known about the aetiology of mitochondrial disorders in the South African population. This study is part of a collaborative study initiated in order to investigate the aetiology of mitochondrial disorders in South African paediatric patients. Patients were previously diagnosed on clinical presentation and/or biochemical enzyme analysis only, without the support of genetic testing. This study was undertaken to elucidate the role of possible mutations in the mtDNA POLG1 gene in a clinically selected paediatric target patient group (TPG). The clinical selection of eight patients from a group of 38 paediatric patients was mainly based on the occurrences of impaired eye function which has previously been associated with possible POLG malfunctioning. The aim of this study was to determine the POLG1 genetic sequence in the selected target patient group and to determine the relative mitochondrial copy number (RMCN) of the entire group of 38 patients.
Results obtained from RMCN analysis of the larger paediatric patient group, suggests that the clinical selection of patients for possible POLG mutations is inadequate. No pathogenic mutations, insertions or deletions were found in the selected TPG, but eight known intronic single nudeotide polymorphisms (SNPs), which include two insertion-deletions, were detected.
No mutations were found in the POLG gene of patients that, based on their clinical profiles, were suspected to have POLG malfunctioning. However, the number of patients investigated in this study was small and therefore these results are not representative of all South African patients. It is therefore suggested that all the South African patients with confirmed mitochondrial disorders should be sequenced for possible POLG gene mutations, before any final conclusions can be drawn.||