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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The familial-genetic relationship between affective and schizophrenic disorders is receiving a re-emergence of interest. The reasons are a series of cross-diagnostic molecular-genetic discoveries: specific alleles in the genes for dysbindin (DTNBP1), neuregulin (NRG1) and DAOA (G72/G30) reveal associations for each of both groups of disorders in the same direction in some but not all reported studies. These findings cannot just be false positives because of confirming metaanalyses. Furthermore there is some pathophysiological support: the mentioned genes are involved in biochemical pathways, which are contributing to both disorders partly in a similar and partly in a different manner. The new levels of evidence enrich the classical continuity/discontinuity debate on the relationship between both groups of disorders.
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PMID:Common risk genes for affective and schizophrenic psychoses. 1851 16

Major psychiatric disorders, including schizophrenia, bipolar disorder and substance addiction, are partly heritable and show a multifactorial pattern of heredity. Although the introduction of explicit diagnostic criteria has improved clinical research on psychiatric disorders, the concept is only of limited use for exploring their genetic underpinnings. On the behavioral level, psychopathological symptoms can hardly separate the many pathophysiological subgroups. Contrary to nosological categories, biologically based phenotypes - referred to as intermediate phenotypes - consisting of neuropsychological, electrophysiological, functional and structural brain imaging parameters, could represent the genetic basis more directly. Thus intermediate phenotypes are being targeted in current molecular genetic investigations. In this article, we review existing data on the effects of genetic variation in the dopamine and serotonin systems (catechol-O-methyltransferase, the serotonin-transporter-linked polymorphic region) on the morphometric, metabolic and functional characteristics of the cerebral cortex and limbic structures. The gene-driven modulation of these brain circuits is discussed with regard to their behavioral correlates and their role for psychiatric diseases. Furthermore, recently identified putative susceptibility genes for schizophrenia (neuregulin 1, dysbindin, G72) are briefly discussed.
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PMID:Genes and neuroimaging: advances in psychiatric research. 1852 Jan 62

Genetic susceptibility plays an important role in the pathogenesis of schizophrenia. Genetic evidence for an association between the dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) and schizophrenia has been repeatedly reported in various populations worldwide. Thus, we performed behavioral analyses on homozygous sandy (sdy) mice, which lack dysbindin-1 owing to a deletion in the Dtnbp1 gene. Our results showed that sdy mice were less active and spent less time in the center of an open field apparatus. Consistent with the latter observation, sdy mice also displayed evidence of heightened anxiety-like response and deficits in social interaction. Compared to wild-type mice, sdy mice displayed lower levels of dopamine, but not glutamate, in the cerebral cortex, hippocampus, and hypothalamus. These findings indicate that sdy mice display a number of behavioral abnormalities associated with schizophrenia and suggest that these abnormalities may be mediated by reductions in forebrain dopamine transmission.
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PMID:Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. 1855 92

The dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, beta-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.
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PMID:The dystrobrevin-binding protein 1 gene: features and networks. 1866 67

Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.
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PMID:Role of glutamate in schizophrenia: integrating excitatory avenues of research. 1875 51

Schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.
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PMID:Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. 1877 65

Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we studied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not significantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activating effect of a low dose of d-amphetamine (2.5 mg/kg i.p.), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced locomotor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants.
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PMID:Behavioral characterization of dysbindin-1 deficient sandy mice. 1898 10

Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenia patients. However the role of specific-genes in the development of cognitive deficit remains unclear. The article aims at reviewing the current studies devoted to association between gene polymorphisms and cognitive dysfunctions in schizophrenic patients. Main attention is drawn to the association between the Val158Met polymorphism of the COMT gene and cognitive traits that has been consistently replicated and has a biological and neuropsychological support. The association studies on the genes for dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase and D-amino acid oxidase activator are reviewed as well.
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PMID:[Molecular genetics of cognitive deficit in schizophrenia]. 1898 32

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.
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PMID:Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS). 1908 8

A number of reports have provided genetic evidence for an association between the DTNBP1 gene (coding dysbindin) and schizophrenia. In addition, sandy mice, which harbor a deletion in the DTNBP1 gene and lack dysbindin, display behavioral abnormalities suggestive of an association with schizophrenia. However, the mechanism by which the loss of dysbindin induces schizophrenia-like behaviors remains unclear. Here, we report that small interfering RNA-mediated knockdown of dysbindin resulted in the aberrant organization of actin cytoskeleton in SH-SY5Y cells. Furthermore, we show that morphological abnormalities of the actin cytoskeleton were similarly observed in growth cones of cultured hippocampal neurons derived from sandy mice. Moreover, we report a significant correlation between dysbindin expression level and the phosphorylation level of c-Jun N-terminal kinase (JNK), which is implicated in the regulation of cytoskeletal organization. These findings suggest that dysbindin plays a key role in coordinating JNK signaling and actin cytoskeleton required for neural development.
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PMID:Dysbindin engages in c-Jun N-terminal kinase activity and cytoskeletal organization. 1909 65


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