Radically truncated MeCP2 rescues Rett syndrome-like neurological defects

Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K.E. , Guy, J., De Sousa, D., Hector, R. D. , Cobb, S. R. and Bird, A. (2017) Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature, 550, pp. 398-401. (doi: 10.1038/nature24058) (PMID:29019980)

147430.pdf - Accepted Version



Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome1. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine2, 3. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners4, including transcriptional co-repressors (for example, the NCoR/SMRT complex5), transcriptional activators6, RNA7, chromatin remodellers8, 9, microRNA-processing proteins10 and splicing factors11. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons12. 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 domain13 and the NCoR/SMRT interaction domain5. 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 evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cobb, Dr Stuart and Gadalla, Dr Kamal and Hector, Dr Ralph
Authors: Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K.E., Guy, J., De Sousa, D., Hector, R. D., Cobb, S. R., and Bird, A.
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN (Online):1476-4687
Published Online:11 October 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 550:398-401
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3003680A gene therapy consortium to develop and evaluate next generation gene therapy approaches in Rett syndromeStuart CobbRett Syndrome Research Trust (RSRT)N/ANP - Centre for Neuroscience