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)

Genetic factors are important in the etiology of schizophrenia. Recent studies have revealed the association between genetic variation of Dysbindin (DTNBP1) and schizophrenia. Dysbindin is one of the essential components of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). BLOC-1 physically interacts with the adaptor protein (AP)-3 complex, which is essential for vesicle or protein sorting. However, it remains largely unknown how BLOC-1 interacts with the AP-3 complex. To investigate the binding mode of BLOC-1 and the AP-3 complex, we examined the relation between Dysbindin and the AP-3 complex and found that Dysbindin formed a complex with the AP-3 complex through the direct binding to its mu subunit. Dysbindin partially co-localized with the AP-3 complex in CA1 and CA3 of mouse hippocampus, and at presynaptic terminals and axonal growth cones of cultured hippocampal neurons. Suppression of Dysbindin results in the reduction of presynaptic protein expression and glutamate release. Thus, Dysbindin appears to participate in the exocytosis or sorting of the synaptic vesicle via direct interaction with the AP-3 complex.
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PMID:Direct interaction of Dysbindin with the AP-3 complex via its mu subunit. 1942 85

Schizophrenia, a severe brain disorder that involves hallucinations, disordered thinking and deficiencies in cognition, has been studied for decades in order to determine the early events that lead to this neurological disorder. In this review, we interpret the developmental and genetic models that have been proposed and treatment options associated with these models. Schizophrenia was initially thought to be hereditary based on studies of high incidence in certain families. Additionally, studies on specific genes such as ZDHHC8 and DTNBP1 seem to suggest susceptibility to the onset of this disorder. However, no single gene variation has been linked to schizophrenia, and recent evidence on sporadic cases of schizophrenia refutes genetics as being a singular cause of the disease. In addition, current data suggests neurodevelopmental or environmental causes such as viral infections and prenatal/perinatal complications. Before any brain disorder can be understood, however, multiple cognitive neuroscientific models that accommodate evidence from many biomedical research fields should be considered, and unfortunately, many of these models are in the earliest stages of development. Consequently, it makes us question whether we are any closer to an adequate understanding of the pathophysiology of schizophrenia.
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PMID:Schizophrenia pathophysiology: are we any closer to a complete model? 1944 74

Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population.
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PMID:Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS). 1947 63

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p=0.00016, allele: p=0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p=0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p=0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.
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PMID:G72 gene is associated with susceptibility to methamphetamine psychosis. 1948 54

Genetic variation in dysbindin 1 (DTNBP1) gene region tagged by SNP rs1018381 exhibits a linkage with cognitive deficits in patients with schizophrenia and healthy subjects. Language production deficits are core features of schizophrenia with more impairment in semantic than lexical verbal fluency tasks. We investigated the link between brain activation and DTNBP1 SNP rs1018381 during semantic verbal fluency task in a German healthy population. 46 healthy subjects genotyped for SNP rs1018381 status were divided in heterozygous risk-allele carriers (T/C) and homozygous non-carriers (C/C). Neural correlates of semantic verbal fluency were investigated with functional magnetic resonance imaging (fMRI). Stronger right hemispherical brain activation in anterior cingulate gyrus (BA 24), superior (BA 22, 38) and middle (BA 21) temporal gyrus was observed in the carriers compared to non-carriers. Brain activations occurred in the absence of task performance differences. No significant correlations were found between personality traits and brain activation differences. The results point to an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on neural correlates of language production. Carriers may exhibit higher processing efforts to reach the same behavioural performance as non-carriers as reflected in activation of schizophrenia-related regions.
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PMID:Genetic variation in schizophrenia-risk-gene dysbindin 1 modulates brain activation in anterior cingulate cortex and right temporal gyrus during language production in healthy individuals. 1949 74

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.
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PMID:The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth. 1954 60

DTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression. Using a matched pairs design in which each of 28 Caucasian schizophrenia cases was matched in age and sex to a normal Caucasian control, Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in dysbindin-1C (but not in dysbindin-1A or -1B) in schizophrenia (P = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the USA. Indeed, no significant correlations were found between case-control differences in any dysbindin-1 isoform and the case-control differences in its encoding mRNA. Consequently, the mean 60% decrease in dysbindin-1C observed in 71% of our case-control pairs appears to reflect abnormalities in mRNA translation and/or processes promoting dysbindin-1C degradation (e.g. oxidative stress, phosphorylation and/or ubiquitination). Given the predominantly post-synaptic localization of dysbindin-1C and known post-synaptic effects of dysbindin-1 reductions in the rodent equivalent of the DLPFC, the present findings suggest that decreased dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.
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PMID:Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. 1961 33

Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10-12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p<0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia.
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PMID:Dysbindin modulates brain function during visual processing in children. 1963 Dec 76

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.
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PMID:Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. 1964 86

Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo- and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty-seven right-handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk-allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2-back vs. 0-back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk-allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of "inefficient" or compensatory DLPFC cognitive control functions.
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PMID:Impact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals. 1965 Jan 39


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