【作者】 许苗菁； 贺荣霓； 宋萍萍； 何勇； 黄伟； 周晓； 顾勇； 潘速跃； 胡亚芳；

【机构】 南方医科大学南方医院神经内科；

【摘要】 Background: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.Method: In this study, we generated AT-hook 1 mutant mice carrying deletion of eight conserved amino acids in AT-hook 1 domain by clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9 technology. Results : Mecp2ΔAT-hook1/y 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. On the molecular basis, Western blot analysis showed increased expression of mutant MeCP2 protein in the cortex. Additionally, histone 3 dimethylation was altered in the cerebrum and the cerebellum. Interestingly, several genes expressed specifically in inhibitory neurons were markedly changed. Conclusion:Taken together, these data demonstrate that AT-hook 1 domain is a critical region for the function of MeCP2 protein.更多还原

【Abstract】 Background: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.Method: In this study, we generated AT-hook 1 mutant mice carrying deletion of eight conserved amino acids in AT-hook 1 domain by clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9 technology. Results : Mecp2ΔAT-hook1/y 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. On the molecular basis, Western blot analysis showed increased expression of mutant MeCP2 protein in the cortex. Additionally, histone 3 dimethylation was altered in the cerebrum and the cerebellum. Interestingly, several genes expressed specifically in inhibitory neurons were markedly changed. Conclusion:Taken together, these data demonstrate that AT-hook 1 domain is a critical region for the function of MeCP2 protein.更多还原