Mechanisms for Microcephaly, Cancer and Autoinflammation

This programme identifies genes causing inherited disorders of the brain. We study how these genes function, using cells and model organisms. Aicardi-Goutières syndrome is a genetic condition in which faults in genes encoding enzymes called nucleases mimic viral infection of the brain. These nucleases may normally clean up naturally produced ‘waste’ DNA and RNA. Failure of this process leads to the body mounting an immune reaction against itself. This immune response mechanism is relevant to common autoimmune diseases such as lupus. So, we are studying these nucleases to understand their normal roles in cells and to establish what happens when these enzymes fail. From studying one of these nucleases, we have found that ribonucleotides, the building blocks of RNA, are also present in DNA. They can be harmful causing damage to the genome and can lead to mutations in cancers. The signature of such mutations may be useful in future in tailoring cancer therapies. We also discover genes that cause primordial dwarfism, conditions with extreme growth failure of the brain and body. Such individuals are the 'smallest people in the world'. These disorders are due to fewer cells being made during development, leading to a smaller person. Identifying primordial dwarfism genes helps diagnose and manage these rare conditions. It also gives insights into how the body regulates growth, perhaps shedding light into why humans are bigger than mice and how our brains evolved to be so large.