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)

The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.
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PMID:Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy. 1287 99

Dysbindin is a coiled-coil-containing protein that was initially identified in a screen for dystrobrevin-interacting proteins. Recently, dysbindin has been shown to be involved in the biogenesis of lysosome-related organelles and is also a major schizophrenia susceptibility factor. Although dysbindin has been implicated in a number of different cellular processes, little is known about its function. To determine the function of dysbindin in muscle, we performed a yeast two-hybrid screen to identify potential interacting proteins. Here we show that dysbindin binds to a novel 413-kDa protein, myospryn, which is expressed in cardiac and skeletal muscle. The transcript encoding myospryn encompasses genethonin-3, a transcript that is down-regulated in muscle from Duchenne muscular dystrophy patients and stretch-responsive protein 553, which is up-regulated in experimental muscle hypertrophy. The C terminus of myospryn contains BBC, FN3, and SPRY domains in a configuration reminiscent of the tripartite motif protein family, as well as the dysbindin-binding site and a region mediating self-association. Dysbindin and myospryn co-immunoprecipitate from muscle extracts and are extensively co-localized. These data demonstrate for the first time that there are tissue-specific ligands for dysbindin that may play important roles in the different disease states involving this protein.
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PMID:Myospryn is a novel binding partner for dysbindin in muscle. 1468 50

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.
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PMID:Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. 1512 15

The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results.
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PMID:The dysbindin gene in major depression: an association study. 1527 41

After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone.
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PMID:[In search of susceptibility genes for schizophrenia]. 1569 Sep 66

Dysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy. Subsequently, genetic studies have implicated variants of the human dysbindin-encoding gene, DTNBP1, in the pathogeneses of Hermansky-Pudlak syndrome and schizophrenia. The protein is a stable component of a multisubunit complex termed BLOC-1 (biogenesis of lysosome-related organelles complex-1). In the present study, the significance of the dystrobrevin-dysbindin interaction for BLOC-1 function was examined. Yeast two-hybrid analyses, and binding assays using recombinant proteins, demonstrated direct interaction involving coiled-coil-forming regions in both dysbindin and the dystrobrevins. However, recombinant proteins bearing the coiled-coil-forming regions of the dystrobrevins failed to bind endogenous BLOC-1 from HeLa cells or mouse brain or muscle, under conditions in which they bound the Dp71 isoform of dystrophin. Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms. Within BLOC-1, dysbindin is engaged in interactions with three other subunits, named pallidin, snapin and muted. We herein provide evidence that the same 69-residue region of dysbindin that is sufficient for dystrobrevin binding in vitro also contains the binding sites for pallidin and snapin, and at least part of the muted-binding interface. Functional, histological and immunohistochemical analyses failed to detect any sign of muscle pathology in BLOC-1-deficient, homozygous pallid mice. Taken together, these results suggest that dysbindin assembled into BLOC-1 is not a physiological binding partner of the dystrobrevins, likely due to engagement of its dystrobrevin-binding region in interactions with other subunits.
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PMID:Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. 1644 87

Extraordinal activation of nigrostriatal and mesolimbic dopaminergic systems (midbrain dopaminergic system) is thought to be one of the most important etiologies for schizophrenia, though the reason why unusual hyperactivation of the dopaminergic system occurs in the schizophrenic brain is quite obscure. Dysbindin, one of the most susceptible genes for schizophrenia, has been reported to be reduced in the schizophrenic brain. In situ hybridization analysis showed the mRNA expression of dysbindin in the mouse substantia nigra. Furthermore, suppression of dysbindin expression in PC12 cells resulted in an increase of the expression of SNAP25, which plays an important role in neurotransmitter release, and increased the release of dopamine. On the other hand, up-regulation of dysbindin expression in PC12 cells showed a tendency to decrease the expression of SNAP25. These data suggest that dysbindin might regulate the dopamine release of the dopaminergic system via modulation of the expression of SNAP25.
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PMID:Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin. 1670 50

Dysbindin (DTNBP1: dystrobrevin binding protein 1), located on 6p22.3, is a candidate susceptibility gene for schizophrenia. Several studies, mostly in Caucasians, have provided evidence for an association between schizophrenia and the gene, although no common polymorphism or haploytpe has been established. In Asian populations, two studies investigated a limited number of single nucleotide polymorphisms (SNPs) of dysbindin and observed support for the association. In the present study, we investigated 12 SNPs of dysbindin, including those examined in previous Asian studies, and the corresponding haplotypes in a Japanese people with schizophrenia. As a result, no significant difference was observed between patients and controls in allelic frequencies or genotypic distributions of the 12 SNPs. Permutation test however showed significant differences in frequencies of the estimated 10-marker haplotypes between patients and controls (global p = 0.006). The present study may provide further support for an association between dysbindin and schizophrenia in Asian populations. The results might be similar to a previous Asian study, but specific haplotypes suggested for the association differed between the studies. Studies with more markers and subjects may be required before firm conclusions can be reached.
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PMID:Association study of the dysbindin (DTNBP1) gene in schizophrenia from the Japanese population. 1687 95

Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.
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PMID:Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. 1693 Jun 38

Dysbindin (DTNBP1) is a positional candidate gene for 6p22.3-linked schizophrenia (SZ). However, so far, no disease-causing alleles have been identified. DTNBP1 is immediately adjacent to JARID2, a member of the ARID (AT-rich interaction domain) family of transcription modulators. We have previously suggested that proteins which bind to AT-rich domains could play a role in SZ pathogenesis. Consequently, we explored the possibility that JARID2 itself could be a candidate gene for 6p22.3-linked SZ. We used a case control design to analyze single nucleotide polymorphisms (SNPs) and insertion/deletion variants affecting AT-rich domains in both the DTNBP1 and JARID2 genes. Three of the DTNBP1 SNPs analyzed had previously been shown to be associated with SZ. We did not detect any significant difference in allele, genotype or haplotype distribution for any of these DTNBP1 markers. However, we did detect a significant difference in allele distribution for a tetranucleotide repeat polymorphism in the JARID2 gene that affects an AT-rich domain. A significant increase in short alleles (less than 11 repeats) was found in patients with SZ (chi(2) = 7.02; P = 0.008). No other JARID2 marker displayed statistically significant allele and genotype distributions. Our findings suggest that JARID2 should be viewed as a candidate gene for 6p22.3-linked SZ.
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PMID:Positive association of schizophrenia to JARID2 gene. 1696 65


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