Uncovering Nuclear Modifiers of mtDNA Mutation Pathogenicity in Mitochondrial Disease
Mitochondrial diseases are a group of genetic disorders that disrupt how the body produces energy. These diseases can cause many different symptoms, but most commonly affect parts of the body that need a lot of energy, such as the brain and muscles. They are the leading cause of neurological disability and death from metabolic problems in children. Mitochondrial diseases are caused by mutations in genes that are needed for mitochondria—the parts of our cells that make energy—to work properly. Despite progress in genetic testing, about half of all children with suspected mitochondrial disease still do not receive a clear genetic diagnosis. Without knowing the exact genetic cause, families are left without answers, and doctors lack information needed to predict outcomes, offer counseling, or access emerging treatments.
This project explores a new explanation for why many children remain undiagnosed. Instead of a single faulty gene causing disease, we think that in some cases two genes may act together to cause disease. While most people are familiar with the nuclear genome, mitochondria have their own small genome called mitochondrial DNA (mtDNA). For mitochondria to work properly, genes from both genomes need to work together. We believe that some children with mitochondrial disease may carry a combination of changes—one in a nuclear gene and another in an mtDNA gene—that together cause disease. This idea, called nuclear-mitochondrial digenic inheritance, could explain why some genetic causes have been missed.
In this study, we will use two strategies to uncover these nuclear-mitochondrial gene interactions. First, we will use cutting-edge laboratory tools to identify nuclear genes that worsen or protect against the effects of damaging mitochondrial mutations in human cells. Second, we will analyze large human genetic datasets to search for combinations of nuclear and mitochondrial genes that are unusually rare or common, suggesting they may cause or protect against disease. This project will provide new ways to identify hidden causes of disease and directly improve genetic diagnosis, clinical care, and treatment for children affected by these devastating conditions.