Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model for a new approach to neuropsychiatric gene linkage is proposed in the context of increased chromosomal breakage which has recently been reported in association with Tourette syndrome, schizophrenia, Rett syndrome and the psychopathology associated with mentally normal, female obligate fra-X carriers. Chromosomal fragility may be connected with the formation of unstable repeat sequences at multiple sites resulting in a continuum of effects, ranging from advantageous evolutionary changes, to more serious neurobehavioural disorders, with neurodegenerative states on the extreme end of the spectrum. The current major problem with phenotype-genotype correlations in complex neuropsychiatric disorders may, therefore, be due to the distance between a postulated breakage-enhancing effect of the primary gene(s), and the continuum of diverse phenotypes resulting from the secondary-gene involvement at a varying number of fragile sites. A unifying view of behavioural alteration, viewed in anthropogenetic context, rather than a DSM-based reductionist approach may be required for the elucidation of psyche-destabilizing genetic changes.
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PMID:A paradigmatic shift in the approach to neuropsychiatric gene linkage may require an anthropogenetic perspective. 877 Oct 44

Fluorescence in situ hybridization (FISH) of DNA-DNA or DNA-RNA using post-mortem brain samples is one approach to study low-level chromosomal aneuploidy and selective expression of specific genes in the brain of patients with neuropsychiatric diseases. We have performed a pilot molecular-cytogenetic analysis of post-mortem brain of schizophrenic patients. Multicolor FISH on two post-mortem brain samples of normal individuals and six schizophrenic individuals (area 10 of cortex) was applied. A set of DNA probes for FISH included: (i) centromeric alphoid DNA probes for chromosomes 7, 8, 13 and 21, 18, X and Y; (ii) classical satellite DNA probes for chromosomes 1 and 16; and (iii) region-specific DNA probes for chromosomes 13, 21 and 22. A statistically significant level of aneuploidy (up to 0.5-4% of neurons) involving chromosomes X and 18 was detected in two post-mortem brains of patients with schizophrenia. These results indicate that low-level chromosomal aneuploidy could be involved in the pathogenesis of schizophrenia. FISH could be applied to extended studies of chromosomal aneuploidy, abnormal patterns of chromosomal organization and functional gene expression in situ in the neurons of the brain in different psychiatric and neurodevelopmental diseases. Schizophrenia and Rett syndrome might be considered as psychiatric diseases of special interest for molecular-cytogenetic analysis as both of them could be associated with mutations in genes involving regulation of neurodevelopmental processes in the brain.
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PMID:Multicolor fluorescent in situ hybridization on post-mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. 1173 70

Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study.
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PMID:MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism. 1521 31

I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader-Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperger syndrome, Rett syndrome, Turner syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome, commonly engender increased relative effects from paternally expressed imprinted genes, or reduced effects from genes favouring maternal interests. Imprinted-gene effects on the etiologies of autistic and psychotic spectrum conditions parallel the diametric effects of imprinted genes in placental and foetal development, in that psychotic spectrum conditions tend to be associated with undergrowth and relatively-slow brain development, whereas some autistic spectrum conditions involve brain and body overgrowth, especially in foetal development and early childhood. An important role for imprinted genes in the etiologies of psychotic and autistic spectrum conditions is consistent with neurodevelopmental models of these disorders, and with predictions from the conflict theory of genomic imprinting.
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PMID:Genomic imprinting in the development and evolution of psychotic spectrum conditions. 1878 62

The epigenetic down-regulation of genes is emerging as a possible underlying mechanism of the GABAergic neuron dysfunction in schizophrenia. For example, evidence has been presented to show that the promoters associated with reelin and GAD67 are down-regulated as a consequence of DNA methyltransferase (DNMT)-mediated hypermethylation. Using neuronal progenitor cells to study this regulation, we have previously demonstrated that DNMT inhibitors coordinately increase reelin and GAD67 mRNAs. Here, we report that another group of epigenetic drugs, histone deacetylase (HDAC) inhibitors, activate these two genes with dose and time dependence comparable with that of DNMT inhibitors. In parallel, both groups of drugs decrease DNMT1, DNMT3A, and DNMT3B protein levels and reduce DNMT enzyme activity. Furthermore, induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. Our data imply that drug-induced promoter demethylation is relevant for maximal activation of reelin and GAD67 transcription. The results suggest that HDAC and DNMT inhibitors activate reelin and GAD67 expression through similar mechanisms. Both classes of drugs attenuate, directly or indirectly, the enzymatic and transcriptional repressor activities of DNMTs and HDACs. These data provide a mechanistic rationale for the use of epigenetic drugs, individually or in combination, as a potential novel therapeutic strategy to alleviate deficits associated with schizophrenia.
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PMID:The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. 1902 85

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.
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PMID:The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. 1946 32

The approval of suberoylanilide hydroxamic acid by the FDA for the treatment of cutaneous T-cell lymphoma in October, 2006 sparked a dramatic increase in the development of inhibitors for the class of enzymes known as the histone deacetylases (HDACs). In recent years, a large number of combination therapies involving histone deacetylase inhibitors (HDACIs) have been developed for the treatment of a variety of malignancies and neurodegenerative disorders. Promising evidence has been reported for the treatment of pancreatic cancer, prostate cancer, and leukemia as well as a number of other previously difficult to treat cancers. Drug combination approaches have also shown promise for the treatment of mood disorders including bipolar disorder and depression. In addition to these drug combination approaches, HDACIs alone have demonstrated effectiveness in the treatment of Parkinson's disease, Alzheimer's disease, Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease, multiple sclerosis, anxiety, and schizophrenia. Adverse inflammatory affects observed with traumatic brain injury and arthritis have also been alleviated by treatment with certain HDACIs. Based on the diverse utility and wide range of mechanistic actions observed with this class of drugs, the future development of better drug combination therapies and more selective HDACIs is warranted.
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PMID:Creating zinc monkey wrenches in the treatment of epigenetic disorders. 1954 31

DNA methylation is an epigenetic mechanism in which the methyl group is covalently coupled to the C5 position of the cytosine residue of CpG dinucleotides. DNA methylation generally leads to gene silencing and is catalyzed by a group of enzymes known as DNA methyltransferases (Dnmt). During development, the epigenome undergoes waves of demethylation and methylation changes. As a result, there are cell type/tissue-specific DNA methylation patterns. Since DNA methylation changes only happen during DNA replication to maintain methylation patterns on hemimethylated DNA or establish new methylation, Dnmt expression generally decreases greatly after cell division. However, significant levels of Dnmts were noticed specifically in postmitotic neurons, suggesting a functional importance of Dnmt in the nervous system. Accumulating evidence showed that DNA methylation correlates with certain neuropsychiatric disorders such as schizophrenia, Rett syndrome, and ICF syndrome. Studies of methyl-CpG-binding proteins, Dnmt inhibitors, and Dnmt knockout mice also explored the key role of DNA methylation in neural development, plasticity, learning, and memory. Though an enzyme exhibiting DNA demethylation capability in vertebrates still remains to be identified, DNA methylation status in the CNS appeared to be reversible at certain genomic loci. This supports a maintenance role of Dnmt to prevent active demethylation in postmitotic neurons. Taken together, DNA methylation provides an epigenetic mechanism of gene regulation in neural development, function, and disorders.
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PMID:The role of DNA methylation in the central nervous system and neuropsychiatric disorders. 1990 Jun 16

Adenosine A(2A) receptors (A(2A)Rs) appear to play important roles in inflammation and in certain diseases of the nervous system. Pharmacological modulation of A(2A)Rs is particularly useful in Parkinson's disease and has been tested in schizophrenia. However, little is known about the regulation of A(2A)R gene (ADORA2A). A bioinformatic analysis revealed the presence of three CpG islands in the 5' UTR region of human ADORA2A. Next, HeLa, SH-SY5Y and U87-MG cells were treated for 48 h with 5 muM 5-azacytidine (Aza). Increased A(2A)R levels were demonstrated in HeLa and SH-SY5Y cells when compared with non-treated cells. No modifications were seen in U87-MG cells. The increased A(2A)R mRNA and protein levels were accompanied by a loss of DNA methylation pattern in HeLa and SH-SY5Y cells, as measured with the SEQUENOM MassArray platform. The Aza treatment also reduced the affinity of a methyl-CpG-binding protein for ADORA2A by quantitative chromatin immunoprecipitation in HeLa cells. Interestingly, A(2A)R levels were reduced by S-adenosyl-l-methionine treatment in U87-MG and methyl-CpG-binding protein affinity was increased for ADORA2A by quantitative chromatin immunoprecipitation. Therefore, these results show for the first time that DNA methylation plays a role in ADORA2A transcription and, subsequently, in constitutive A(2A)R cell surface levels.
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PMID:DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. 2000 25

Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome.
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PMID:Pharmacology of epigenetics in brain disorders. 2001 91


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