Functional studies of mutant nucleases in a genetic model of inflammatory and viral disease.

Aicardi Goutihres Syndrome (AGS) closely resembles viral illnesses such as congenital rubella and cytomegalovirus infections. However it is caused by a faulty gene instead of viral infection. We have recently identified several genes that cause this condition. These genes encode enzymes called nucleases. Nucleases are found in all cells in the body and their job is to breakdown DNA and RNA into their component parts. The discovery of a relationship of these particular nucleases to the body's immune response was unexpected. It may be that these nucleases clean up naturally produced 'waste' DNA and RNA. Mutation in these genes could result in failure of this process, leading to the body mounting an immune reaction against itself, and so mimicking the effects of a viral infection. This immune response mechanism is also relevant to other common autoimmune diseases, such as lupus. We propose to study these enzymes to understand their normal roles in cells and to establish what happens when these enzymes fail due to gene mutations in AGS patient cells. These studies will provide us with a more detailed understanding of autoimmune disease processes and how the human body responds to viral infections.