Human Molecular Genetics Advance Access published online on September 6, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh282
© 2004 by Oxford University Press
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1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
* To whom correspondence should be addressed. E-mail: hzoghbi{at}bcm.tmc.edu.
Mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2), 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 wildtype 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 approximately two fold wild-type levels, demonstrated onset of phenotypes around ten weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After twenty weeks of age, however, these mice developed seizures, became hypoactive, and approximately 30% of them died by one year of age. These data demonstrate that MeCP2's 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.
Article
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
2 Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030
3 Department of Neurology, Baylor College of Medicine, Houston, Texas 77030
4 Howard Hughes Medical Institute
5 Department of Pathology, Baylor College of Medicine, Houston, Texas 77030
6 Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030; Department of Neurology, Baylor College of Medicine, Houston, Texas 77030
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030; Howard Hughes Medical Institute
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