Transmission and recurrence risks in mtDNA disease: The unique way in which mitochondrial DNA (mtDNA) is transmitted makes genetic counselling difficult. Dramatic changes in level of mutant mtDNA are attributable to a "genetic bottleneck" whereby a small number of mtDNAs become the founders for the offspring. We are studying the basis of this bottleneck in families and embryos, and are developing novel approaches to genetic counselling of mtDNA diseases, namely oocyte sampling and pre-implantation genetic diagnosis.
Diseases of mtDNA maintenance: Control of mitochondrial copy number may be central to the pathogenesis of mtDNA disorders such as MtDNA depletion syndrome (MDS), Autosomal dominant Progressive External Ophthalmoplegia (AdPEO), Autosomal recessive Progressive External Ophthalmoplegia (ArPEO) and MyoNeuroGastroIntestinal Encephalomyopathy (MNGIE). These newly characterised mtDNA diseases are caused by mutations in autosomal genes, many of which are associated with a reduced quantity of defective mtDNA in affected tissues. We have therefore developed a method for quantitating the rate of mtDNA synthesis in cell lines derived from patients with these diseases. We are using this to study the 16189 variant, autosomally inherited defects in mtDNA maintenance and the basic science of mtDNA replication. We have also used this method to demonstrate consistent abnormalities in mtDNA synthesis in cell lines derived from such patients. Understanding the molecular mechanisms of these disorders may improve genetic counselling, and suggest novel therapies.
MtDNA variants in common multi-factorial diseases: We demonstrated that a common polymorphism, the mtDNA "16189 variant" is a risk factor for low birth weight to placental ratio, type2 diabetes and other multifactorial disorders. Because the 16189 variant has arisen many times independently, these associations are likely to be causal and not due to a founder effect. We are studying the molecular basis for these associations, which imply interactions of nuclear and mitochondrial genomes.


  • –present
    Professor, University of Oxford