Radically truncated MeCP2 rescues Rett syndrome-like neurological defects

• Published in: Nature (London) 2017-10, Vol.550 (7676), p.398-401
• Main Authors: Tillotson, Rebekah, Selfridge, Jim, Koerner, Martha V., Gadalla, Kamal K. E., Guy, Jacky, De Sousa, Dina, Hector, Ralph D., Cobb, Stuart R., Bird, Adrian
• Format: Article
• Language: English
• Subjects: 13/31; 14; 14/63; 3T3 Cells; 42; 42/44; 631/208/176/1988; 631/208/366/1373; 64; 64/60; Animals; Brain - metabolism; DNA - metabolism; Gene mutation; Gene therapy; Genetic aspects; Genetic Complementation Test; Genetic Therapy - methods; Health aspects; HeLa Cells; Humanities and Social Sciences; Humans; letter; Male; Methods; Methyl-CpG-Binding Protein 2 - chemistry; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; multidisciplinary; Mutation, Missense; Nervous system diseases; Phenotype; Protein Domains - genetics; Protein Stability; Rett syndrome; Rett Syndrome - genetics; Rett Syndrome - pathology; Rett Syndrome - physiopathology; Rett Syndrome - therapy; Science; Sequence Deletion; Transduction, Genetic
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24058

Analysis of the minimal functional unit for MeCP2 protein shows that its function is to recruit the NCoR/SMRT co-repressor complex to methylated sites on chromatin, which may have use in designing strategies for gene therapy of Rett syndrome. MeCP2 to the Rett-scue Rett syndrome is a neurological disorder caused by mutations in the MECP2 gene, which tend to be clustered in two discrete regions of the protein (MeCP2). In this report, the authors parse the minimal form of MeCP2 that is required to retain its functionality, and interrogate which of its many proposed roles is relevant for Rett syndrome progression. The identification of a minimal functional unit for MeCP2 could be helpful in the design of therapeutic strategies for gene therapy for Rett syndrome. Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome 1 . The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine 2 , 3 . Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners 4 , including transcriptional co-repressors (for example, the NCoR/SMRT complex 5 ), transcriptional activators 6 , RNA 7 , chromatin remodellers 8 , 9 , microRNA-processing proteins 10 and splicing factors 11 . Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons 12 . At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain 13 and the NCoR/SMRT interaction domain 5 . Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite ev