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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human chromosome 15q11-13 is a complex locus containing imprinted genes as well as a cluster of three GABA(A) receptor subunit (GABR) genes-GABRB3, GABRA5 and GABRG3. Deletion or duplication of 15q11-13 GABR genes occurs in multiple human neurodevelopmental disorders including Prader-Willi syndrome (PWS), Angelman syndrome (AS) and autism. GABRB3 protein expression is also reduced in Rett syndrome (RTT), caused by mutations in MECP2 on Xq28. Although Gabrb3 is biallelically expressed in mouse brain, conflicting data exist regarding the imprinting status of the 15q11-13 GABR genes in humans. Using coding single nucleotide polymorphisms we show that all three GABR genes are biallelically expressed in 21 control brain samples, demonstrating that these genes are not imprinted in normal human cortex. Interestingly, four of eight autism and one of five RTT brain samples showed monoallelic or highly skewed allelic expression of one or more GABR gene, suggesting that epigenetic dysregulation of these genes is common to both disorders. Quantitative real-time RT-PCR analysis of PWS and AS samples with paternal and maternal 15q11-13 deletions revealed a paternal expression bias of GABRB3, while RTT brain samples showed a significant reduction in GABRB3 and UBE3A. Chromatin immunoprecipitation and bisulfite sequencing in SH-SY5Y neuroblastoma cells demonstrated that MeCP2 binds to methylated CpG sites within GABRB3. Our previous studies demonstrated that homologous 15q11-13 pairing in neurons was dependent on MeCP2 and was disrupted in RTT and autism cortex. Combined, these results suggest that MeCP2 acts as a chromatin organizer for optimal expression of both alleles of GABRB3 in neurons.
Hum Mol Genet 2007 Mar 15
PMID:15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. 1733 70

Rett syndrome (RTT), a leading cause of mental retardation with autistic features in females, is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). RTT is characterized by a diverse set of neurological features that includes cognitive, motor, behavioral and autonomic disturbances. The diverse features suggest that specific neurons contribute to particular phenotypes and raise the question whether restoring MeCP2 function in a cell-specific manner will rescue some of the phenotypes seen in RTT. To address this, we generated transgenic mice expressing inducible MeCP2 under the control of the brain-specific promoters calcium/calmodulin-dependent protein kinase II (CamKII) or neuron-specific enolase (Eno2) and bred them onto mouse models lacking functional MeCP2. Expression of normal MeCP2 in either CamKII or Eno2 distribution was unable to prevent the appearance of most of the phenotypes of the RTT mouse models. These results suggest that most RTT phenotypes are caused either by disruption of complex neural networks involving neurons throughout the brain or by disruption of the function of specific neurons outside of the broad CamKII or Eno2 distribution.
Hum Mol Genet 2007 Oct 01
PMID:Cell-specific expression of wild-type MeCP2 in mouse models of Rett syndrome yields insight about pathogenesis. 1763 39

Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.
Mol Psychiatry 2008 Jan
PMID:Advances in behavioral genetics: mouse models of autism. 1784 15

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Three SOCS genes, SOCS-1, 2 and 3, have been identified and their sequences analyzed in an economically important fish, rainbow trout (Oncorhynchus mykiss, Walbaum). In general, these three SOCS molecules are well conserved especially in the SRC homology 2 and the SOCS domains, with sequence identities between trout and mammals ranging from 41 to 42, 50 to 51, and 58 to 61% for SOCS-1, 2 and 3, respectively. The identities within fish species are slightly higher, with sequence identities between trout and the other fish species at 44-46, 64-70, and 71-76% for SOCS-1, 2 and 3, respectively. All the SOCS-1, as well as all the SOCS-2 or 3 molecules from different species are grouped together in phylogenetic tree analysis with high bootstrap support, with the fish molecules in each type grouping closely together. The expression of the trout SOCS-1, 2 and 3 genes are detectable by real-time PCR in all the eight tissues studied; the gills, skin, muscle, liver, spleen, head kidney, intestine and brain. SOCS-1 is highly expressed in intestine, head kidney, spleen, gills and skin. SOCS-2 is highly expressed in brain, head kidney, muscle, spleen, gills, skin and intestine. The expression of SOCS-3 is the highest among the three SOCS genes in all the tissues except in intestine, brain and liver. The modulation of SOCS gene expression is shown to be cytokine and cell type dependent. While interferon-gamma up-regulates the expression of all the three SOCS genes in both the fibroid RTG-2 and the monocyte/macrophage RTS-11 cell lines, interleukin-1beta only up-regulates SOCS gene expression in the RTG-2 cell line, with little, if any, effect in the RTS-11 cell line.
Mol Immunol 2008 Mar
PMID:Rainbow trout suppressor of cytokine signalling (SOCS)-1, 2 and 3: molecular identification, expression and modulation. 1792 Jan 26

Both fragile X syndrome and Rett syndrome are commonly associated with autism spectrum disorders and involve defects in synaptic plasticity. MicroRNA is implicated in synaptic plasticity because fragile X mental retardation protein was recently linked to the microRNA pathway. DNA methylation is also involved in synaptic plasticity since methyl CpG-binding protein 2 (MeCP2) is mutated in patients with Rett syndrome. Here we report that expression of miR-184, a brain-specific microRNA repressed by the binding of MeCP2 to its promoter, is upregulated by the release of MeCP2 after depolarization. The restricted release of MeCP2 from the paternal allele results in paternal allele-specific expression of miR-184. Our finding provides a clue to the link between the microRNA and DNA methylation pathways.
Hum Mol Genet 2008 Apr 15
PMID:MeCP2-dependent repression of an imprinted miR-184 released by depolarization. 1820 56

Rett syndrome is an X-linked neurological condition affecting almost exclusively girls that is caused by mutations of the MECP2 gene. Recent studies have shown that transgenic delivery of MeCP2 function to Mecp2-deficient male mice can improve their Rett-like behavior. However, as the brain of a Rett girl contains a mosaic of MeCP2 expressing and non-expressing neurons, and the over-expression of MeCP2 in neurons can induce a severe progressive neurological phenotype, testing whether functional rescue can be achieved by gene re-introduction strategies in a female model of Rett syndrome is warranted. To address this, we generated transgenic mice expressing an epitope-tagged Mecp2 transgene in forebrain neurons. These mice over-express MeCP2 protein at about 1.6 times normal levels in cortex and develop impaired motor behavior by 9-12 months of age. To test whether forebrain-targeted MeCP2 restoration would improve behavior in female Mecp2(-/+) mice, we crossed these transgenics with Mecp2(-/+) mice and examined the behavioral properties of the female rescue mice for 1 year. These assessments revealed that the diminished rearing activity, impaired mobility and the diminished locomotive activity of female Mecp2(-/+) mice were restored to wild-type levels in the rescue mice. These results show that improvement of Rett-like behavior can be achieved in Mecp2(-/+) females by targeted gene re-introduction without inducing deficits relating to MeCP2 over-expression.
Hum Mol Genet 2008 May 15
PMID:Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice. 1822 99

Over 200 mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) are known to cause Rett syndrome (RTT), a multiphasic neurodevelopmental disorder that results in motor and cognitive impairments; however, little is known about the neurobiology of RTT. Here, we employ the MeCP2(308/y) mouse model of RTT to investigate the course of the neuronal defects imparted by MeCP2 mutation. Using the olfactory system as a neurodevelopmental model, we describe an acute but transient defect in olfactory sensory neuron maturation during synaptogenesis and elaboration of the glomerular neuropil. This defect is overcome through compensatory responses that restore homeostasis. However, a chronic problem in glomerular organization emerges, which eventually leads to increased neuronal apoptosis. This multiphasic course comprising acute developmental and chronic defects in synaptogenesis and maintenance may represent the neurobiological correlates of clinical RTT, and suggests that different therapeutic strategies may be appropriate at different clinical stages of this disease.
Mol Cell Neurosci 2008 Apr
PMID:MeCP2 mutation causes distinguishable phases of acute and chronic defects in synaptogenesis and maintenance, respectively. 1829 6

MeCP2 is an essential transcriptional repressor that mediates gene silencing through binding to methylated DNA. Binding specificity has been thought to depend on hydrophobic interactions between cytosine methyl groups and a hydrophobic patch within the methyl-CpG-binding domain (MBD). X-ray analysis of a methylated DNA-MBD cocrystal reveals, however, that the methyl groups make contact with a predominantly hydrophilic surface that includes tightly bound water molecules. This suggests that MeCP2 recognizes hydration of the major groove of methylated DNA rather than cytosine methylation per se. The MeCP2-DNA complex also identifies a unique structural role for T158, the residue most commonly mutated in Rett syndrome.
Mol Cell 2008 Feb 29
PMID:MeCP2 binding to DNA depends upon hydration at methyl-CpG. 1831 90

MeCP2 is an abundant protein that binds to methylated cytosine residues in DNA and regulates transcription. Mutations in MECP2 cause Rett syndrome, a severe neurological disorder that affects approximately 1:10 000 females. Mice lacking MeCP2 have been generated and constitute important models of Rett syndrome. However, it is yet unclear whether certain physiological events are sensitive to a decrease, rather than a complete lack of MeCP2. Here we report that a Mecp2 floxed allele (Mecp2(lox)) that was generated to allow conditional mutagenesis behaves as a hypomorph and the corresponding mutant mice exhibit phenotypical alterations including body weight gain, motor abnormalities and altered social behavior. Our data reinforce the view that the central nervous system is extremely sensitive to MeCP2 expression levels and suggest that the 3'-UTR of Mecp2 might contain important elements that contribute to the regulation of its stability or processing.
Hum Mol Genet 2008 Jun 15
PMID:Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice. 1832 65

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.
Hum Mol Genet 2008 Jun 15
PMID:A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. 1832 64


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