Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes

Ross, P. D. et al. (2016) Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes. Human Molecular Genetics, 25(20), pp. 4389-4404. (doi:10.1093/hmg/ddw269) (PMID:28173151)

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Abstract

Rett Syndrome (RTT) is a severe genetic disorder resulting from mutations in the X-linked MECP2 gene. MeCP2 protein is highly expressed in the nervous system and deficiency in the mouse central nervous system alone recapitulates many features of the disorder. This suggests that RTT is primarily a neurological disorder, although the protein is reportedly widely expressed throughout the body. To determine whether aspects of the RTT phenotype that originate in non-neuronal tissues might have been overlooked, we generated mice in which Mecp2 remains at near normal levels in the nervous system, but is severely depleted elsewhere. Comparison of these mice with wild type and globally MeCP2-deficient mice showed that the majority of RTT-associated behavioural, sensorimotor, gait and autonomic (respiratory and cardiac) phenotypes are absent. Specific peripheral phenotypes were observed, however, most notably hypo-activity, exercise fatigue and bone abnormalities. Our results confirm that the brain should be the primary target for potential RTT therapies, but also strongly suggest that some less extreme but clinically significant aspects of the disorder arise independently of defects in the nervous system.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ross, Mr Paul and Cobb, Dr Stuart and Kamal, Dr Bushra and McCarroll, Dr Charlotte and Loughrey, Dr Christopher and Bailey, Dr Mark and Bahey, Mrs Noha and Tanner, Professor K
Authors: Ross, P. D., Guy, J., Selfridge, J., Kamal, B., Bahey, N., Tanner, E., Gillingwater, T. H., Jones, R. A., Loughrey, C. M., McCarroll, C. S., Bailey, M. E.S., Bird, A., and Cobb, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:09 August 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Human Molecular Genetics 25(20): 4389-4404
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
644651Developing and evaluating novel gene therapy approaches in Rett syndromeStuart CobbScottish Executive Health Department (SEHHD-CSO)ETM/334INP - CENTRE FOR NEUROSCIENCE
500141Doctoral Training Grant 2009-16Julian DowBiotechnology and Biological Sciences Research Council (BBSRC)BB/F016700/1RI MOLECULAR CELL & SYSTEMS BIOLOGY