Department of Neurology, Nanfang Hospital, the Southern Medical University, Guangzhou, PR China.
Department of Neurology, Zhujiang Hospital, the Southern Medical University, Guangzhou, Guangdong, PR China.
Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):347-358. doi: 10.1016/j.bbadis.2017.10.022. Epub 2017 Oct 24.
MECP2 is the causative gene for autism spectrum disorders, including Rett syndrome, a regressive neurodevelopmental rare disease mainly occurring in girls. Except for the distinct methyl-CpG binding domain and the transcriptional repression domain in MeCP2, three AT-hook-like domains have recently been identified. Several mutations in AT-hook 1 domain have been reported in autism cases or Rett database. However, the role of AT-hook 1 domain is still unclear. In this study, we generated a mouse line carrying deletion of eight conserved amino acids in AT-hook 1 domain by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. Mecp2 mutant male mice exhibited low locomotor activity, motor incoordination and cognitive deficit. In addition, these mutant mice exhibited increased anxiety. Moreover, pain insensitivity was noted in the mutant males. However, the social interactions were unaffected in AT-hook 1 mutant mice. Thinner CA1 region of the hippocampus was observed in the mutant mice. On the molecular basis, Western blot analysis showed increased expression of mutant MeCP2 protein in the cortex. Additionally, several genes expressed specifically in inhibitory neurons were markedly changed in the cerebrum. Taken together, these data demonstrate that disruption of AT-hook 1 domain in MeCP2 caused behavioral abnormality in mice, which suggests that AT-hook 1 is a critical region for the function of MeCP2 protein.
MECP2 是自闭症谱系障碍（包括雷特综合征）的致病基因，雷特综合征是一种退行性神经发育性罕见疾病，主要发生在女孩中。除了 MeCP2 中独特的甲基-CpG 结合域和转录抑制域外，最近还发现了三个 AT 钩样结构域。在自闭症病例或雷特数据库中已经报道了 AT 钩 1 结构域中的几个突变。然而，AT 钩 1 结构域的作用仍不清楚。在这项研究中，我们通过聚类规则间隔短回文重复序列（CRISPR）/Cas9 技术生成了一种携带 AT 钩 1 结构域中八个保守氨基酸缺失的小鼠系。Mecp2 突变雄性小鼠表现出运动活性降低、运动不协调和认知缺陷。此外，这些突变小鼠表现出焦虑增加。此外，突变雄性小鼠表现出疼痛感觉迟钝。然而，AT 钩 1 突变小鼠的社交互动没有受到影响。突变小鼠的海马 CA1 区变薄。在分子基础上，Western blot 分析显示突变 MeCP2 蛋白在皮质中的表达增加。此外，大脑中几种特异性表达于抑制性神经元的基因明显改变。总之，这些数据表明 MeCP2 中 AT 钩 1 结构域的破坏导致小鼠出现行为异常，这表明 AT 钩 1 是 MeCP2 蛋白功能的关键区域。
