Genetic factors modulating the expression of mitochondrial disease.
Description: Mitochondrial disorders affect ~1 in 5000 of the population and cause progressive, incurable diseases which often result in premature death. The primary genetic defect affects either nuclear DNA or mitochondrial DNA (mtDNA), and ultimately leads to a biochemical defect of ATP synthesis. However, despite having the same basic biochemical basis, mitochondrial disorders have an enormously variable clinical presentation and disease course. I will test the hypothesis that nuclear and mitochondrial ge netic factors modulate the clinical expression of mitochondrial disorders, thus explaining the variable phenotype. Specifically, I will: (i) Define the sub-cellular mechanism responsible for the mtDNA genetic bottleneck during female germ cell development in a germ-line model in vitro, and validate these findings in vivo in both mice and humans, leading to the identification of compounds which influence transmission. (ii) Comprehensively characterise the nuclear gene defects in a natio nal cohort of patients with Mendelian mitochondrial disorders using whole-exome and restricted whole-genome sequencing. This will identify new mitochondrial disease genes that will undergo functional validation using tissue-specific cell lines differentiated from patient-derived induced pluripotent stem cells (iPSCs). (iii) Use state-of-the-art genomics to identify nuclear genetic factors that modulate the phenotype of the primary mitochondrial DNA disease, Leber hereditary optic neuropathy. Studying the functional consequences of the disrupted nuclear genes in tissue-specific lineages differentiated from patient-derived iPSCs will provide the first insight into the tissue-specificity of mitochondrial disorders. These three areas are inter-related in patients with mitochondrial diseases. By characterising the mechanisms, I aim to identify novel approaches to prevention and treatment.
Funder: Wellcome Trust
Amount: £1,282,000
Funding type: grant
Funder scheme: Genetics, Genomics and Population Research
Start date: 2013-10-01
End date: 2018-12-01
Investigator: Patrick F. Chinnery
Institution: Newcastle University
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 140
Funder award ID: 101876
OpenAlex ID: G5036397130