Mechanisms for Microcephaly, Cancer and Autoinflammation

这个项目确定了导致大脑遗传性疾病的基因。我们研究这些基因是如何发挥作用的，使用细胞和模式生物。Aicardi-Goutières综合征是一种遗传性疾病，其中编码称为核酸酶的酶的基因中的缺陷模拟了大脑的病毒感染。这些核酸酶通常可以清除自然产生的“废物”DNA和RNA。这一过程的失败导致身体对自己产生免疫反应。这种免疫反应机制与常见的自身免疫性疾病如狼疮有关。因此，我们正在研究这些核酸酶，以了解它们在细胞中的正常作用，并确定当这些酶失效时会发生什么。通过研究这些核酸酶中的一种，我们发现核糖核苷酸，RNA的构建单元，也存在于DNA中。它们可能是有害的，对基因组造成损害，并可能导致癌症突变。这种突变的特征可能在未来的癌症治疗中很有用。我们还发现了导致原始侏儒症的基因，这种疾病导致大脑和身体的极度发育障碍。这些人是“世界上最小的人”。这些疾病是由于在发育过程中产生的细胞较少，导致人变小。识别原始侏儒症基因有助于诊断和管理这些罕见的疾病。它还提供了关于身体如何调节生长的见解，也许可以解释为什么人类比老鼠大，以及我们的大脑是如何进化到如此之大的。

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.