Human Molecular Genetics Advance Access originally published online on September 6, 2004
Human Molecular Genetics 2004 13(21):2679-2689; doi:10.1093/hmg/ddh282
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
1Department of Molecular and Human Genetics, 2Department of Neuroscience, 3Department of Neurology and 4Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA and 5Howard Hughes Medical Institute, Chevy Chase, MD, USA
Received June 22, 2004; Accepted August 25, 2004
Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2Tg1, which expresses MeCP2 at 
2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.
* To whom correspondence should be addressed. Tel: +1 7137986523; Fax: +1 7137988728; Email: hzoghbi{at}bcm.tmc.edu
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