Identification of nuclear factors modulating the clinical phenotype of m.3243A>G-related mitochondrial disease

Mitochondria are responsible for converting food energy into cellular energy. They rely on genetic information from two sources: DNA on chromosomes in the nucleus and their own DNA (mtDNA). Mutations in either can cause disease. The most common mtDNA mutation, m.3243A>G, causes a devastating syndrome that results in uncontrolled seizures, strokes and early death. However, large numbers of m.3243A>G-carriers have different symptoms, including diabetes and deafness. The mutation can affect any organ, at any age with any degree of severity.

Family studies suggest that differences in nuclear chromosomes influence clinical outcome. This project aims to identify these using a unique group of m.3243A>G carriers from 140 unrelated families by searching nuclear chromosomes for areas that are shared more frequently in patients with similar symptoms using linkage and association analysis, sequencing the DNA of patients to identify variations in the nuclear chromosomes that cause differences in clinical outcome, and characterising these variants, showing how they cause these differences. A statistical model to estimate disease outcome based on genetic risk factors will then be developed.

The discovery of genetic risk factors for m.3243A>G-related disease will improve our understanding of this common mitochondrial disease and allow clinicians to tailor patient treatment and advice.