title: A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Houston, TX 77030, USA.
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Samaco
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Sharyl
authors.initials: S
authors.lastname: Fyffe
authors.forename: Hsiao-Tuan
authors.initials: HT
authors.lastname: Chao
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Neul
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007858:Learning; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009425:Nesting Behavior; D010146:Pain / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance; D013216:Reflex, Startle; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D045442:Rotarod Performance Test; D012919:Social Behavior
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms