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

DNA methylation is an epigenetic modification that is implicated in transcriptional silencing. It is becoming increasingly clear that both correct levels and proper interpretation of DNA methylation are important for normal development and function of many organisms, including humans. In this review we focus on recent advances in understanding how proteins that bind to methylated DNA recognize their binding sites and translate the DNA methylation signal into functional states of chromatin. Although the function of methyl-CpG binding proteins in transcriptional repression has been attributed to their cooperation with co-repressor complexes, additional roles for these proteins in chromatin compaction and spatial organization of nuclear domains have also been proposed. Finally, we provide a brief overview of how methyl-CpG proteins contribute to human disease processes such as Rett syndrome and cancer.
Cell Mol Life Sci 2008 May
PMID:Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin? 1832 51

The gastrin-releasing peptide receptor (GRPR) was implicated for the first time in the pathogenesis of Autism spectrum disorders (ASD) by Ishikawa-Brush et al. [Ishikawa-Brush et al. (1997): Hum Mol Genet 6: 1241-1250]. Since this original observation, only one association study [Marui et al. (2004): Brain Dev 26: 5-7] has further investigated, though unsuccessfully, the involvement of the GRPR gene in ASD. With the aim of contributing further information to this topic we have sequenced the entire coding region and the intron/exon junctions of the GRPR gene in 149 Italian autistic patients. The results of this study led to the identification of four novel point mutations, two of which, that is, C6S and L181F, involve amino acid changes identified in two patients with ASD and Rett syndrome, respectively. Both the leucine at position 181 and the cysteine at position 6 are strongly conserved in vertebrates. C6S and L181F mutant proteins were expressed in COS-7 and BALB/3T3 cells, but they did not affect either GRP's binding affinity or its potency for stimulating phospholipase C-mediated production of inositol 1,4,5-trisphosphate. In summary, our results do not provide support for a major role of the GRPR gene in ASD in the population of patients we have studied. However, there is a potential role of C6S and L181F mutations on GRPR function, and possibly in the pathogenesis of the autistic disorders in the two patients.
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PMID:Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders. 1839 81

Interferon regulatory factors (IRF) 3 and 7 in mammals are known to be crucial in regulating the type I interferon (IFN) response to viral infection as part of transcriptional complexes binding to IRF-binding elements (IRF-Es) and interferon stimulatory response elements (ISREs) within IFN and interferon-stimulated genes (ISGs). Here we report the sequencing and characterization of full-length cDNA homologues of rainbow trout (rt)IRF7 and, for the first time in fish, IRF3. RtIRF3 consists of 2127 bp with a 159 bp 5'-UTR-containing two upstream AUGs and a 573 bp 3'-UTR. RtIRF7 was found to be 2055 bp, with a 102 bp 5'-UTR and a 705 bp 3'-UTR. The open reading frames (ORFs) translate into 464 amino acid and 415 amino acid proteins, respectively, each possessing a putative DNA-binding domain (DBD) containing a tryptophan cluster, which is characteristic of all IRF family members. The presence of putative IRF association domain (IAD)s, serine-rich C terminal domains (poorly conserved in trout IRF3), and phylogenetic analysis places the two genes in the IRF3 subfamily. Both genes were found to be upregulated by poly I:C, type I recombinant rainbow trout (r) IFN (second isoform, type I rIFN), type II rIFN (rIFNgamma), LPS, and rIL-1beta in the trout macrophage cell line, RTS-11. Poly I:C and type I rIFN also induced IRF3 and IRF7 expression in a trout fibroblast cell line (RTG-2). Transient transfection of RTG-2 cells with each IRF fused to GFP revealed a predominant cytoplasmic distribution found most intensely around the nucleus and, to a lesser extent, within cell nuclei. Transient transfection of rtIRF3 in the Mx-1-luciferase reporter cell line, RTG-P1, revealed a modest increase in luciferase activity relative to the vehicle control, which was lost in cells over-expressing a DBD-truncated form of rtIRF3. Both full-length and DBD-truncated forms of rtIRF7 increased reporter activity relative to the control, although to a non-significant extent. Electromobility shift assays (EMSAs) did not reveal a specific interaction between each IRF and the ISRE element found in the Mx-1 promoter, although the Mx-1 ISRE bound specifically to endogenous transcriptional complexes. These data support the premise that rtIRF3 and rtIRF7 are important molecules in the regulation of antiviral responses in fish, with the impact of rIFNgamma on rtIRF3/7 expression implying a role for these IRFs in immune processes other than type I IFN-driven antiviral responses.
Mol Immunol 2008 Dec
PMID:Molecular characterization of IRF3 and IRF7 in rainbow trout, Oncorhynchus mykiss: functional analysis and transcriptional modulation. 1880 86

Mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), cause the neurodevelopmental disorder Rett syndrome (RTT). Although MECP2 mutations are rare in idiopathic autism, reduced MeCP2 levels are common in autism cortex. MeCP2 is critical for postnatal neuronal maturation and a modulator of activity-dependent genes such as Bdnf (brain-derived neurotropic factor) and JUNB. The activity-dependent early growth response gene 2 (EGR2), required for both early hindbrain development and mature neuronal function, has predicted binding sites in the promoters of several neurologically relevant genes including MECP2. Conversely, MeCP2 family members MBD1, MBD2 and MBD4 bind a methylated CpG island in an enhancer region located in EGR2 intron 1. This study was designed to test the hypothesis that MECP2 and EGR2 regulate each other's expression during neuronal maturation in postnatal brain development. Chromatin immunoprecipitation analysis showed EGR2 binding to the MECP2 promoter and MeCP2 binding to the enhancer region in EGR2 intron 1. Reduction in EGR2 and MeCP2 levels in cultured human neuroblastoma cells by RNA interference reciprocally reduced expression of both EGR2 and MECP2 and their protein products. Consistent with a role of MeCP2 in enhancing EGR2, Mecp2-deficient mouse cortex samples showed significantly reduced EGR2 by quantitative immunofluorescence. Furthermore, MeCP2 and EGR2 show coordinately increased levels during postnatal development of both mouse and human cortex. In contrast to age-matched Controls, RTT and autism postmortem cortex samples showed significant reduction in EGR2. Together, these data support a role of dysregulation of an activity-dependent EGR2/MeCP2 pathway in RTT and autism.
Hum Mol Genet 2009 Feb 01
PMID:Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. 1900 Sep 91

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a dominant mutation in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Neuroanatomically, RTT is characterized by a reduction in dendritic arborization and perikaryal size in the brain. MECP2 binds methylated promoters and facilitates assembly of a multiprotein repressor complex that includes Sin3A and the histone deacetylases HDAC1/HDAC2. MeCP2 has recently been found to be downregulated in autistic spectrum disorders such as Angelman syndrome (AS) and RTT, which share some phenotypic manifestations. We have conducted expression analysis of cytoskeleton-related genes in brain tissue of RTT and AS patients. Striking examples of genes with reduced expression were TUBA1B and TUBA3 that encode the ubiquitous alpha-tubulin and the neuronal specific alpha-tubulin, respectively. In accordance with the downregulation of expression of these genes, we have observed a reduction in the level of the corresponding protein product-tyrosinated alpha-tubulin. Low levels of alpha-tubulin and deteriorated cell morphology were also observed in MeCP2(-/y) MEF cells. The effects of MeCP2 deficiency in these cells were completely reversed by introducing and expressing the human MeCP2 gene. These results imply that MeCP2 is involved in the regulation of neuronal alpha-tubulin and add molecular evidence that reversal of the effects of MeCP2 deficiency is achievable. This raises hopes for a cure of Rett syndrome and related MeCP2 deficiency disorders of the autistic spectrum.
Hum Mol Genet 2009 Apr 15
PMID:MeCP2 involvement in the regulation of neuronal alpha-tubulin production. 1917 78

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder, is caused mainly by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Although more than 200 different MECP2 mutations have been identified throughout the gene, 7 of those (p.R133C, p.T158M, p.R168X, p.R255X, p.R270X, p.R294X, and p.R306C) account for up to two-thirds of pathogenic mutations in RTT patients. A rapid and efficient screening strategy for these mutations can be used as a preliminary step for genetic diagnosis of RTT. The current protocols used for this purpose are of high cost and require special equipment. We have designed a simpler multiplex amplification refractory mutation system (ARMS)-PCR strategy that allows identification of these common MECP2 mutant alleles in four PCR reactions. The assay was tested in 14 RTT patients who were previously genotyped using PCR-restriction fragment length polymorphism and DNA sequencing. A complete concordance was observed between the results of the two methods. The multiplex ARMS-PCR does not require any special equipment, and it provides rapid, reproducible, and cost-effective detection of common MECP2 mutations. The assay can be carried out efficiently in a standard molecular genetics laboratory and suitable as a preliminary screen for all patients with RTT diagnosis.
Genet Test Mol Biomarkers 2009 Feb
PMID:A multiplexed ARMS-PCR approach for the detection of common MECP2 mutations. 1930 69

Patients with classical Rett show an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they enter a short period of developmental stagnation followed by a rapid regression in language and motor development. Purposeful hand use is often lost and replaced by repetitive, stereotypic movements. Rett syndrome (RTT) is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). The aim of this study was to search for mutations in MECP2 gene in two Tunisian patients affected with RTT. The results of mutation analysis revealed mutations in exon 4 of MECP2 gene in the two patients. In one patient we identified a new mutation consisting of a deletion of four bases (c.810-813delAAAG), which led to a frame shift and generated a premature stop codon (p.Lys271Arg fs X15) in transcriptional repression domain-nuclear localization signal (TRD-NLS) domain of MeCP2 protein. With regard to the second patient, a previously described transition (c.916C>T) that changed an arginine to a cysteine residue (p.R306C) in TRD domain of MeCP2 protein was revealed. In conclusion, a new and a known de novo mutation in MECP2 gene were revealed in two Tunisian patients affected with RTT.
Genet Test Mol Biomarkers 2009 Feb
PMID:A novel MECP2 gene mutation in a Tunisian patient with Rett syndrome. 1930 83

A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
Hum Mol Genet 2009 Jul 01
PMID:Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. 1936 96

Rett syndrome (RS) is an X-linked dominant neurodevelopment disorder with normal prenatal and postnatal development till 6-18 months, followed by stagnation and regression of acquired skills. RS primarily manifests in females, and there are a few reports with males having RS. Sporadic or de novo mutations of the methyl CpG binding protein 2 (MECP2) gene have been reported in 70-90% of affected girls. Conventional methods such as fluorescence in situ hybridization, real-time PCR, southern blotting, multiplex ligation-dependent probe amplification, and DNA sequencing have been previously reported for the detection of insertions or deletions in the MECP2 gene. Here, we report detection of two deletions of 44 bp (c.1157_1200del44 or p.L386fs) and 38 bp (c.1151_1188del38 or p.P384fs) in exon 4 or C-terminal segment (CTS) region of MECP2 using a simple PCR technique that is rapid, accurate, and cost effective as compared to other techniques. The deletions were detected by routine PCR amplification followed by 2% agarose gel electrophoresis. We suggest that a simple PCR can easily detect deletions in the hotspot CTS region of the MECP2 gene and can be used for routine molecular diagnostics of RS.
Genet Test Mol Biomarkers 2009 Apr
PMID:Rapid detection of deletions in hotspot C-terminal segment region of MECP2 by routine PCR method: report of two classical Rett syndrome patients of Indian origin. 1937 Dec 29

Cell adhesion molecules at neuronal synapses regulate diverse aspects of synaptic development, including axo-dendritic contact establishment, early synapse formation, and synaptic maturation. Recent studies have identified several synaptogenic adhesion molecules. The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. NGLs interact with the abundant postsynaptic density (PSD) protein, PSD-95, and other postsynaptic proteins, including NMDA receptors. These interactions are thought to couple synaptic adhesion events to the assembly of synaptic proteins. In addition, NGL proteins regulate axonal outgrowth and lamina-specific dendritic segmentation, suggesting that the NGL-dependent adhesion system is important for the development of axons, dendrites, and synapses. Consistent with these functions, defects in NGLs and their ligands are associated with impaired learning and memory, hyperactivity, and an abnormal acoustic startle response in transgenic mice, and schizophrenia, bipolar disorder, and Rett syndrome in human patients.
Mol Cell Neurosci 2009 Sep
PMID:The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. 1946 32


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