BRPF1基因在儿童智力障碍发生中的分子机制

The prevalence of intellectual disability in children or adolescents is about 2%. Intellectual disability is not only a heavy burden on individuals and families, but also brings a series of problems to society and education. Most intellectual disabilities are caused by genetic factors. So far, hundreds of genes have been associated with intellectual disability. Within them, epigenetic regulators are one of the most important categories. Bromodomain and PHD Finger-containing protein 1 (BRPF1) is a scaffold protein and an activator of the three acetyltransferase KAT6A / KAT6B / KAT7 complexes. Two recent reports published in the American Journal of Human Genetics found 16 cases of BRPF1 heterozygous mutations leading to intellectual disability in children. Our published work explained the molecular mechanisms of some symptoms such as growth retardation, white matter abnormality and spinal fusion. To further understand the neurobiological basis of intellectual disability caused by BRPF1 mutations, this proposal is based on the Brpf1 transgenic mouse models. Firstly, effect of haploinsufficiency of Brpf1 gene on the occurrence of intellectual disability will be studied. Secondly, molecular and regulatory mechanisms of Brpf1 gene on the morphology and function of GABAergic interneurons and hippocampal CA1 pyramidal neurons will be explored. Through this project we can better understand the molecular mechanisms of acetylation activator BRPF1 on regulation of intelligence development, and establish intellectual disability mouse models mimicking BRPF1 mutations in human for further drug screening and development.

智力障碍在儿童或青少年中的患病率达2%。不仅造成患者个人和家庭的沉重负担，也给社会和教育带来一系列问题。大多数的智力障碍由遗传因素造成。至今发现的数百个智力障碍相关基因中，表观遗传调控剂是其中重要的一类。溴结构域和PHD锌指蛋白1（BRPF1）是三个乙酰化酶KAT6A/KAT6B/KAT7复合物的支架蛋白和激活剂。近期两篇报道发现16例BRPF1杂合突变导致儿童智力障碍。我们已发表的工作解释了患者出现生长发育迟缓、白质异常和脊椎融合等症状的分子机制。为了理解BRPF1突变造成智力障碍的神经生物学基础，本课题使用Brpf1转基因小鼠模型，研究该基因单倍剂量不足对智力障碍发生的影响；探索该基因调控GABA能中间神经元和海马CA1锥体神经元形态和功能的分子机制。预期通过本课题的研究更好地理解BRPF1这一类乙酰化激活剂调控智力发育的分子机制，建立BRPF1智力障碍小鼠模型用于后期药物筛选和开发。