Human Molecular Genetics Advance Access originally published online on March 4, 2008
Human Molecular Genetics 2008 17(12):1718-1727; doi:10.1093/hmg/ddn062
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A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome
1 Department of Molecular and Human Genetics 2 Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, MS 225, Houston, TX 77030, USA 3 Department of Physiology, University of Alberta, Alberta, Canada 4 Section of Neurology, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, MS 225, Houston, TX 77030, USA 5 Howard Hughes Medical Institute, Alberta, Canada
* To whom correspondence should be addressed at: One Baylor Plaza, MS 225, Houston TX 77030, USA. Tel: +1 7137986523; Fax: +1 7137988727; Email: jneul{at}bcm.tmc.edu
Received November 20, 2007; Revised February 20, 2008; Accepted February 27, 2008
Rett Syndrome, an X-linked dominant neurodevelopmental disorder characterized by regression of language and hand use, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2). Loss of function mutations in MECP2 are also found in other neurodevelopmental disorders such as autism, Angelman-like syndrome and non-specific mental retardation. Furthermore, duplication of the MECP2 genomic region results in mental retardation with speech and social problems. The common features of human neurodevelopmental disorders caused by the loss or increase of MeCP2 function suggest that even modest alterations of MeCP2 protein levels result in neurodevelopmental problems. To determine whether a small reduction in MeCP2 level has phenotypic consequences, we characterized a conditional mouse allele of Mecp2 that expresses 50% of the wild-type level of MeCP2. Upon careful behavioral analysis, mice that harbor this allele display a spectrum of abnormalities such as learning and motor deficits, decreased anxiety, altered social behavior and nest building, decreased pain recognition and disrupted breathing patterns. These results indicate that precise control of MeCP2 is critical for normal behavior and predict that human neurodevelopmental disorders will result from a subtle reduction in MeCP2 expression.
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