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)

There is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community-Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high-risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538-P1583 (P = 0.048), P1320-P1757 (P = 0.034), and rs2619538-P1583-P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538-P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.
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PMID:Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients. 1729 Apr 45

New genes consistently associated with schizophrenia include NRG1, Akt, DISC-1 and dysbindin-1. Since these genes participate in neurotransmission, neuroplasticity and neurodevelopment it has not been easy to elucidate which of these roles are abnormal in patients with schizophrenia. Neurite formation is identified as a crucial stage in development, and it is proposed that a defect in neurite formation originating from abnormally encoded proteins by these new genes could be at least an in vitro marker that reflects the most consistent molecular and neuroanatomical findings in schizophrenia. A systematic review of the literature linking the process of neurite formation to genes with replicated evidence that supported their association with schizophrenia was conducted. In addition, an outline of the process of neurite formation was included. Neurite formation was shown to be induced by neuregulins, the product of the gene NRG1. The activation of Akt, a serine/threonine kinase, promoted neurite formation in six independent studies. Conversely, two studies found that Akt inhibits neurite outgrowth. Stronger evidence supporting an association with the new genes related to schizophrenia and neurite formation comes from DISC-1. Defects in DISC-1 protein were shown to directly alter the process of neurite formation. Dysbindin-1 has not yet been directly implicated in neurite outgrowth. These findings suggest that the proteins encoded by NRG1, Akt and DISC-1 are implicated in the process of neurite formation in cellular models as well as, at least in part, animal models during development. Abnormalities in this process could have potential etiologic implications for schizophrenia. Direct evidence, however, of abnormal neurite formation in patients with schizophrenia is still missing. Limitations to this model are identified.
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PMID:New genes associated with schizophrenia in neurite formation: a review of cell culture experiments. 1744 Apr 37

Schizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.
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PMID:High dopamine turnover in the brains of Sandy mice. 1754 56

Dysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.
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PMID:Is there protective haplotype of dysbindin gene (DTNBP1) 3 polymorphisms for major depressive disorder. 1796 51

The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.
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PMID:Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. 1798 3

Delineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across psychotic disorders and may particularly be associated with negative symptoms, i.e. affective flattening, alogia and avolition. We have previously published evidence of association with a dysbindin risk haplotype derived from alleles C-A-T at SNPs P1655 (rs2619539), P1635 (rs3213207) and SNP66961 (rs2619538) in two independent schizophrenia (SZ) case-control samples. The C-A-T haplotype impacts at the level of gene function and phenotype: the haplotype indexes lower cortical expression of the dysbindin gene in post-mortem SZ brain samples and haplotype carriers show greater deficits in spatial working memory and early visual processing than non-carrier SZ patients. The aim of this study was to establish if the C-A-T dysbindin risk haplotype is associated with a specific clinical symptom profile. We investigated the relationship between the haplotype and PANSS-derived symptom factors in 262 individuals with schizophrenia/schizoaffective disorder using principal components analysis (PCA) and analysis of variance (ANOVA). Dysbindin risk carriers scored significantly less than non-carriers on the 'hostility/excitability' factor (F 1,196=8.468; p=.004), with a trend for higher negative symptom scores. This suggests that risk variation at the dysbindin gene may contribute to a more prototypical SZ presentation with less severe excitement/manic symptoms and more negative symptoms.
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PMID:A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis. 1816 12

In a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25-p24. The 6p region contains Dysbindin (DTNBP1), considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1 and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic re-examination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1 and its association with schizophrenia, using a HapMap-based gene-tagging approach. We genotyped 39 tSNPs in a sample of 336 cases and 172 controls of Anglo-Irish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control sample were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5' region. Neither global haplotype tests, nor specific analysis of the "risk" haplotype previously reported in an ethnically related population, the Irish high-density schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our sample. The framework and results of this study should facilitate further attempts at re-analysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation.
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PMID:Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes. 1831 70

Neurodevelopmental disturbance may underlie the pathogenesis of major mental disorders, including autism and schizophrenia, based on evidence in epidemiology, clinical psychiatry, brain imaging, and neuropathology. This notion is further supported by the fact that many of genetic susceptibility factors for these disorders have key roles in neurodevelopment. Majority of these genetic factors, such as Neuroligins, SHANK3, Neureglin-1, Dysbindin, and Disrupted-in-Schizophrenia-1 (DISC1) are associated with "synapse." Therefore, "synapse" is one of the most promising sites of convergence in regard to molecular pathways for these mental conditions. In this review, we will summarize the updates of schizophrenia and autism research, with an emphasis on neurodevelopmental disturbances.
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PMID:[Neurodevelopmental disturbance in the pathogenesis of major mental disorders]. 1842 86

Whereas Dysbindin is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. (J Autism Dev Disord 35:831-838, 2005) reported an association between Dysbindin and PMA in US-Caucasian individuals with childhood-onset psychosis. In a sample of 222 adult-onset schizophrenia inpatients from Germany, we could not detect an association between PMA and 36 SNPs in Dysbindin. Our results suggest that genetic variation in Dysbindin may not contribute to the schizophrenia phenotype with an onset beyond childhood. Further studies including even larger samples and more SNPs may be warranted to clarify the relationship between Dysbindin and PMA.
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PMID:Brief report: no association between premorbid adjustment in adult-onset schizophrenia and genetic variation in Dysbindin. 1847 58

Dysbindin gene (DTNBP1) has been associated with schizophrenia, but literature findings are inconsistent, and further analyses are required. This study is aimed to investigate if a set of DTNBP1 variations might influence clinic psychotic phenotype or treatment response in a sample of 240 Korean schizophrenic in-patients. Four variants have been selected (rs3213207; rs1011313; rs16876759; rs2619522) on the basis of previous findings of association with schizophrenia, bipolar disorder and antidepressant response. Single marker analysis gave marginal results. Haplotype analysis identified a significant association between A-A (rs3213207(A/G), rs1011313(A/G)) haplotype and lower PANSS total and positive scores at baseline (p=0.01; 0.02) and at discharge (p=0.008; 0.005). Covariate analysis revealed a more stable significant association between A-A haplotype and baseline scores. These results suggest a protective effect of A-A haplotype on psychotic positive symptoms at baseline.
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PMID:DTNBP1 haplotype influences baseline assessment scores of schizophrenic in-patients. 1856


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