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Title: Mitochondrial DNA Mutations in Human Disease
Author: Swalwell, Helen
ISNI:       0000 0001 3493 1098
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2007
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Pathogenic mutations in mitochondrial DNA (mtDNA) are recognised as an important cause of disease, and in many cases lead to well-characterised clinical syndromes. However in many cases the clinical phenotypes associated with mutations in mtDNA are highly variable and the genotype-phenotype correlation is not straightforward. The pathogenesis of mtDNA mutations in many cases remains poorly understood and as such, studies aimed at understanding the expression of mtDNA disease Will benefit genetic counselling, lead to more accurate estimations of mtDNA disease prevalence in popul~tions and hopefully lead to the development ofrational treatments. ,./' In collaboration with Dr. David Thorburn (Murdoch Children's Research Institute, Melbourne), the molecular basis of 15 paediatric patients with a diagnosis of complex I .deficiency has been investigated. These results demonstrate that following rigorous criteria to diagnose complex I deficiency, <25% of cases of paediatric complex I deficiency can be attributed to pathogenic mutations in mtDNA. Due to the highly polymorphic nature of mtDNA, the pathogenicity of any identified mutation must be established using well-defined published criteria. The pathogenicity of four rare/novel mutations in mt-tRNA genes is confirmed and the clinical and ' biochemical consequences of these mutations are investigated in these families. There is increasing evidence that additional homoplasmic variants can playa role in the expression of well-characterised pathogenic mutations. The role of a specific homoplasmic variant, m.7472A>C over the expression of the well-characterised pathogenic mtDNA mutation, m.7472Cins is investigated using both patient studies and transmitochondrial cybrid clones as a model for determining the functional consequences of these changes in an in vitro system. These results provide evidence that additional mutations in mtDNA can influence the expression of pathogenic mutations. Some mt-tRNA mutations are clearly inherited throughout several generations, whereas others arise sporadically and show little or no evidence of transmission. The features of a numb~r of published pathogenic mt-tRNA mutations have been evaluated in order to look for any characteristics that may determine transmission. Whilst the majority of features of these mutations show no correlation with the likelihood of transmission, one factor shows clear correlation. If the mutation is present in the patient's muscle but absent in blood, then the mutation is likely to have arisen sporadically in that patient, and is unlikely to be transmitted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available