Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.
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 MeCP2(Tg1), which expresses MeCP2 at approximately 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 approximately 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.
Collins
Ann L
AL
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Levenson
Jonathan M
JM
Vilaythong
Alexander P
AP
Richman
Ronald
R
Armstrong
Dawna L
DL
Noebels
Jeffrey L
JL
David Sweatt
J
J
Zoghbi
Huda Y
HY
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004594:Electrophysiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D051783:Methyl-CpG-Binding Protein 2; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics*; D013997:Time Factors; D014960:X Chromosome
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins