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Title: Impact of the nuclear proteome on mitochondrial disorders
Author: Neeve, Vivieene C. M.
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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Mitochondrial disease comprises a large group of clinically heterogeneous disorders resulting from inefficient energy production due to both mitochondrial and nuclear mutations. For the majority of cases the underlying genetic defect remains unknown with potentially over 1000 nuclear genes that could result in a mitochondrial disorder. The current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. The involvement of these nuclear genes in mitochondrial disorders was the focus of this study. The first part of the study investigated modifying factors influencing the clinical presentation of patients with a common single homozygous mutation p.A467T in the mitochondrial polymerase y gene, POLG. The POLG promoter region, chromosomal haplotype and genes involved in mtDNA maintenance, ANT1, PEO1 and POLG2, were screened for variants, however, no pathogenic or possibly modifying variants were found. The role of mtDNA haplogroup as a modifying factor was also assessed and highlighted that patients with mtDNA haplogroup U showed a significantly reduced risk of developing epilepsy. The second part of the study investigated paediatric patients with combined respiratory chain deficiency. Previous analysis has excluded defects such as mtDNA mutations and depletion and mutations in routinely screened known pathogenic nuclear genes. Mitochondrial function was assessed in 18 patient cell lines then patients from consanguineous parents or with obvious cellular defects were selected for further analysis. Exome sequencing of a child with Leigh syndrome detected two heterozygous pathogenic mutations in the MTFMT gene. Exome sequencing of a further patient highlighted a homozygous possible disease causing mutation in ZNF5ll, segregating with disease and not present in control populations. Results indicate that a thorough clinical, genetic and functional work-up can help to identify the primary defect or the disease pathomechanism in mitochondrial disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available