28 results on '"Dystrophin-Associated Proteins"'
Search Results
2. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth
- Author
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Ghiani, CA, Starcevic, M, Rodriguez-Fernandez, IA, Nazarian, R, Cheli, VT, Chan, LN, Malvar, JS, de Vellis, J, Sabatti, C, and Dell'Angelica, EC
- Subjects
Schizophrenia ,Mental Health ,Brain Disorders ,Genetics ,Neurosciences ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Neurological ,Analysis of Variance ,Animals ,Animals ,Newborn ,Carrier Proteins ,Cattle ,Cells ,Cultured ,Dysbindin ,Dystrophin-Associated Proteins ,Embryo ,Mammalian ,Gene Expression Regulation ,Developmental ,Hippocampus ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mutation ,Nerve Tissue Proteins ,Neurites ,Neurons ,Protein Binding ,Protein Transport ,Qa-SNARE Proteins ,Recombinant Proteins ,SNARE Proteins ,Synaptosomal-Associated Protein 25 ,Vesicle-Associated Membrane Protein 2 ,schizophrenia ,DTNBP1 ,pallidin ,synaptosomal-associated protein ,biological plausibility ,neurite extension ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
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.
- Published
- 2010
3. Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2
- Author
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Dmitry, Prokopenko, Sanghun, Lee, Julian, Hecker, Kristina, Mullin, Sarah, Morgan, Yuriko, Katsumata, Michael W, Weiner, David W, Fardo, Nan, Laird, Lars, Bertram, Winston, Hide, Christoph, Lange, and Rudolph E, Tanzi
- Subjects
Whole Genome Sequencing ,Alzheimer Disease ,Tumor Suppressor Proteins ,Dystrophin-Associated Proteins ,Neuropeptides ,Humans ,Dithionitrobenzoic Acid ,Genetic Predisposition to Disease ,Genomics ,Guanylate Kinases ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study - Abstract
Alzheimer's disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values10
- Published
- 2021
4. Dysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53
- Author
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Guanghui Wang, Xiaochuan Ma, Cheng Fu, Erkang Fei, and Haigang Ren
- Subjects
Cytoplasm ,Transcription, Genetic ,Neurite ,Coronin ,Nerve Tissue Proteins ,Rats, Sprague-Dawley ,Mice ,Mice, Neurologic Mutants ,Cellular and Molecular Neuroscience ,Transcription (biology) ,RNA interference ,Two-Hybrid System Techniques ,Neurites ,Animals ,Humans ,RNA, Small Interfering ,Nuclear protein ,Molecular Biology ,Cells, Cultured ,Cerebral Cortex ,Mice, Knockout ,Neurons ,Gene knockdown ,biology ,Dysbindin ,Microfilament Proteins ,HEK 293 cells ,Nuclear Proteins ,Rats ,Specific Pathogen-Free Organisms ,Cell biology ,Mice, Inbred C57BL ,Psychiatry and Mental health ,HEK293 Cells ,rab GTP-Binding Proteins ,Dystrophin-Associated Proteins ,biology.protein ,RNA Interference ,Tumor Suppressor Protein p53 ,Carrier Proteins - Abstract
Genetic variations in the DTNBP1 gene (encoding the protein dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. Previous studies have indicated that dysbindin-1 functions in the regulation of synaptic activity. Recently, dysbindin-1 has also been documented to be involved in neuronal development. In this study, we identified necdin as a binding partner of dysbindin-1 using a yeast two-hybrid screen. Dysbindin-1 recruits necdin to the cytoplasm, thereby attenuating the repressive effects of necdin on p53 transcriptional activity. Knockdown of dysbindin-1, like knockdown of p53, greatly decreases the expressions of the p53 target genes coronin 1b and rab13, which are required for neurite outgrowth. Moreover, overexpression of p53 restores the neurite outgrowth blocked by dysbindin-1 knockdown. In brains of dysbindin-1 null mice (the sandy strain), p21, Coronin 1b and Rab13 levels are reduced. Furthermore, primary cultured cortical neurons from sandy mice display neurite outgrowth defects when compared with those from wild-type mice. Thus, our data provide evidence that dysbindin-1 has an important role in neurite outgrowth through its regulation of p53's transcriptional activity.
- Published
- 2011
5. Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation
- Author
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Koh-ichi Nagata, Tomoyasu Shinoda, Ikuko Iwamoto, K Sudo, Rika Morishita, Hidenori Ito, and K Okamoto
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Gene isoform ,Dendritic spine ,Dendritic Spines ,Blotting, Western ,Morphogenesis ,Wiskott-Aldrich Syndrome Protein, Neuronal ,Dendritic spine morphogenesis ,Nerve Tissue Proteins ,Biology ,Hippocampal formation ,Hippocampus ,Postsynapse ,Cellular and Molecular Neuroscience ,Animals ,RNA, Small Interfering ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Neurons ,Gene knockdown ,Dysbindin ,Age Factors ,Rats ,Wiskott-Aldrich Syndrome Protein Family ,Blot ,Psychiatry and Mental health ,Multiprotein Complexes ,Dystrophin-Associated Proteins ,Synapses ,Schizophrenia ,Carrier Proteins ,Neuroscience - Abstract
Genetic variations in dysbindin-1 (dystrobrevin-binding protein-1) are one of the most commonly reported variations associated with schizophrenia. As schizophrenia could be regarded as a neurodevelopmental disorder resulting from abnormalities of synaptic connectivity, we attempted to clarify the function of dysbindin-1 in neuronal development. We examined the developmental change of dysbindin-1 in rat brain by western blotting and found that a 50 kDa isoform is highly expressed during the embryonic stage, whereas a 40 kDa one is detected at postnatal day 11 and increased thereafter. Immunofluorescent analyses revealed that dysbindin-1 is enriched at the spine-like structure of primary cultured rat hippocampal neurons. We identified WAVE2, but not N-WASP, as a binding partner for dysbindin-1. We also found that Abi-1, a binding molecule for WAVE2 involved in spine morphogenesis, interacts with dysbindin-1. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. RNA interference-mediated knockdown of dysbindin-1 led to the generation of abnormally elongated immature dendritic protrusions. The present results indicate possible functions of dysbindin-1 at the postsynapse in the regulation of dendritic spine morphogenesis through the interaction with WAVE2 and Abi-1.
- Published
- 2010
6. Dysbindin-1 genotype effects on emotional working memory
- Author
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Claudia Wolf, Margaret C. Jackson, Johannes Thome, David Edmund Johannes Linden, and Christian Kissling
- Subjects
Male ,Emotions ,Neuropsychological Tests ,Hippocampal formation ,Brain mapping ,Functional Laterality ,0302 clinical medicine ,Gene Frequency ,Image Processing, Computer-Assisted ,Brain Mapping ,0303 health sciences ,Brain ,Cognition ,Middle Aged ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Dysbindin ,Memory, Short-Term ,Pattern Recognition, Visual ,Schizophrenia ,Female ,Psychology ,Adult ,Genotype ,genetic imaging ,dysbindin ,Cognitive neuroscience ,Polymorphism, Single Nucleotide ,Article ,working memory ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,emotional faces ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Chi-Square Distribution ,Working memory ,Recognition, Psychology ,medicine.disease ,Oxygen ,schizophrenia ,Functional imaging ,Face ,Dystrophin-Associated Proteins ,Linear Models ,Carrier Proteins ,Neuroscience ,Photic Stimulation ,030217 neurology & neurosurgery - Abstract
We combined functional imaging and genetics to investigate the behavioral and neural effects of a dysbindin-1 (DTNBP1) genotype associated with the expression level of this important synaptic protein, which has been implicated in schizophrenia. On a working memory (WM) task for emotional faces, participants with the genotype related to increased expression showed higher WM capacity for happy faces compared with the genotype related to lower expression. Activity in several task-related brain areas with known DTNBP1 expression was increased, including hippocampal, temporal and frontal cortex. Although these increases occurred across emotions, they were mostly observed in areas whose activity correlated with performance for happy faces. This suggests effects of variability in DTNBP1 on emotion-specific WM capacity and region-specific task-related brain activation in humans. Synaptic effects of DTNBP1 implicate that altered dopaminergic and/or glutamatergic neurotransmission may be related to the increased WM capacity. The combination of imaging and genetics thus allows us to bridge the gap between the cellular/molecular and systems/behavioral level and extend the cognitive neuroscience approach to a comprehensive biology of cognition.
- Published
- 2009
7. COMT-Dysbindin epistatic interaction
- Author
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Francesco Papaleo, J.H. Callicott, M C Burdick, and Daniel R. Weinberger
- Subjects
Genetics ,Dysbindin ,Prefrontal Cortex ,Epistasis, Genetic ,Neuroimaging ,Biology ,Catechol O-Methyltransferase ,Magnetic Resonance Imaging ,Epistatic interaction ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Dystrophin-Associated Proteins ,Humans ,Carrier Proteins ,Molecular Biology - Published
- 2014
8. DISC1 causes associative memory and neurodevelopmental defects in fruit flies
- Author
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Atsushi Kamiya, Tetsuya Ando, Ken Honjo, Mai Ando, Hiroaki Mochizuki, Kazuki Kurita, Akira Sawa, Katsuo Furukubo-Tokunaga, Kojiro Takayama, Himani Pandey, and Yuko Arai
- Subjects
0301 basic medicine ,Scaffold protein ,dendrites ,Protein domain ,Synaptogenesis ,Nerve Tissue Proteins ,axons ,medicine.disease_cause ,Article ,Animals, Genetically Modified ,memory ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Protein Domains ,synapse ,medicine ,Animals ,Drosophila Proteins ,Humans ,Molecular Biology ,DISC1 ,Neurons ,Mutation ,biology ,Dysbindin ,Brain ,biology.organism_classification ,Psychiatry and Mental health ,030104 developmental biology ,Drosophila melanogaster ,Neurodevelopmental Disorders ,Mushroom bodies ,Dystrophin-Associated Proteins ,Synapses ,Drosophila ,Neural development ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.
- Published
- 2013
9. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth
- Author
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Marta Starcevic, Esteban C. Dell'Angelica, Ramin Nazarian, J. de Vellis, Jemily S. Malvar, Chiara Sabatti, Cristina A. Ghiani, Imilce A. Rodriguez-Fernandez, L N Chan, and Veronica T. Cheli
- Subjects
Vesicle-Associated Membrane Protein 2 ,DTNBP1 ,biological plausibility ,Hippocampus ,Mice ,0302 clinical medicine ,Syntaxin ,susceptibility gene ,neurite extension ,Cells, Cultured ,Mice, Knockout ,Neurons ,0303 health sciences ,synaptosomal-associated protein ,Qa-SNARE Proteins ,Dysbindin ,Gene Expression Regulation, Developmental ,Recombinant Proteins ,Transport protein ,Cell biology ,Psychiatry and Mental health ,Protein Transport ,Synaptosomal-Associated Protein 25 ,SNARE Proteins ,syntaxin ,Protein Binding ,Neurite ,Nerve Tissue Proteins ,Biology ,Synaptic vesicle ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Neurites ,Animals ,Molecular Biology ,030304 developmental biology ,Analysis of Variance ,pallidin ,Embryo, Mammalian ,Mice, Inbred C57BL ,schizophrenia ,Animals, Newborn ,Dystrophin-Associated Proteins ,Mutation ,Cattle ,Organelle biogenesis ,Carrier Proteins ,Neuroscience ,030217 neurology & neurosurgery ,primary cell culture - Abstract
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.
- Published
- 2009
10. The dystrobrevin-binding protein 1 gene: features and networks
- Author
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Jingchun Sun, Kenneth S. Kendler, Zhongming Zhao, Dawn L. Thiselton, Brien P. Riley, and An-Yuan Guo
- Subjects
Gene isoform ,Genetics ,Haplotype ,Dysbindin ,Gene regulatory network ,Single-nucleotide polymorphism ,Biology ,Phenotype ,Interactome ,Polymorphism, Single Nucleotide ,Article ,Evolution, Molecular ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Dystrophin-Associated Proteins ,Animals ,Humans ,Carrier Proteins ,Molecular Biology ,Gene - Abstract
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.
- Published
- 2008
11. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia
- Author
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Paul J. Whiting, Vincent Collura, Kenji Mizuguchi, Henning Hermjakob, Jean-Christophe Rain, L. M. Camargo, Samuel Kerrien, Timothy P. Bonnert, and Nicholas J. Brandon
- Subjects
Psychosis ,Schizophrenia (object-oriented programming) ,Nerve Tissue Proteins ,Interactome ,Cellular and Molecular Neuroscience ,DISC1 ,Cognition ,Interaction network ,Risk Factors ,Two-Hybrid System Techniques ,medicine ,Humans ,Molecular Biology ,Cytoskeleton ,NDEL1 ,biology ,Dysbindin ,Biological Transport ,medicine.disease ,Psychiatry and Mental health ,Dystrophin-Associated Proteins ,Synapses ,biology.protein ,Schizophrenia ,Psychology ,Carrier Proteins ,Neuroscience ,Cell Division - Abstract
Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein–protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called ‘DISC1 interactome’ contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
- Published
- 2006
12. Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations
- Author
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Robin M. Murray, X. Ma, Huaqing Meng, Xiehe Liu, Qiang Wang, P Yates, Pak C. Sham, Neil Walker, Feng Zhang, David A. Collier, Xun Hu, Tao Li, Xueli Sun, Caroline Crombie, Wei Deng, and D. St Clair
- Subjects
Genetic Markers ,Male ,Psychosis ,Linkage disequilibrium ,China ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Cellular and Molecular Neuroscience ,Risk Factors ,medicine ,SNP ,Humans ,Allele ,Molecular Biology ,Alleles ,Genetics ,Haplotype ,Dysbindin ,medicine.disease ,Psychiatry and Mental health ,Haplotypes ,Scotland ,Case-Control Studies ,Dystrophin-Associated Proteins ,Schizophrenia ,Chromosomes, Human, Pair 6 ,Female ,Carrier Proteins - Abstract
The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.
- Published
- 2005
13. Family-based association study of DTNBP1 in 6p22.3 and schizophrenia
- Author
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Jinbo B Fan, N. F. Gu, Yongyong Shi, Lin He, Y. L. Xing, Jun Xia Tang, X. W. Li, G. Y. Feng, J. G. Shi, and Jian Zhou
- Subjects
Adult ,Family Health ,Male ,medicine.medical_specialty ,Family based association ,Schizophrenia (object-oriented programming) ,Dysbindin ,Biology ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Dystrophin-Associated Proteins ,medicine ,Schizophrenia ,Humans ,Chromosomes, Human, Pair 6 ,Female ,Psychiatry ,Carrier Proteins ,Molecular Biology - Published
- 2003
14. Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families
- Author
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Kenneth S. Kendler, Dermot Walsh, Y Jiang, Francis A. O'Neill, B. P. Riley, Patrick F. Sullivan, and E J C G van den Oord
- Subjects
Genetic Markers ,Linkage disequilibrium ,Psychosis ,Northern Ireland ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Evolution, Molecular ,Cellular and Molecular Neuroscience ,Risk Factors ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Phylogeny ,Genetics ,Binding protein ,Haplotype ,Dysbindin ,Tag SNP ,medicine.disease ,Psychiatry and Mental health ,Haplotypes ,Genetic marker ,Dystrophin-Associated Proteins ,Schizophrenia ,Carrier Proteins ,Ireland - Abstract
A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.
- Published
- 2003
15. Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.
- Author
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Papaleo F, Burdick MC, Callicott JH, and Weinberger DR
- Subjects
- Alleles, Animals, Carrier Proteins biosynthesis, Carrier Proteins genetics, Catechol O-Methyltransferase biosynthesis, Dysbindin, Dystrophin-Associated Proteins, Functional Neuroimaging, Gene Expression Regulation genetics, Gene Expression Regulation physiology, Homozygote, Humans, Magnetic Resonance Imaging, Male, Maze Learning physiology, Mice, Mice, Knockout, Mutation, Carrier Proteins physiology, Catechol O-Methyltransferase genetics, Catechol O-Methyltransferase physiology, Epistasis, Genetic, Memory, Short-Term physiology, Prefrontal Cortex physiology
- Abstract
Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes--catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))--implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits.
- Published
- 2014
- Full Text
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16. COMT-Dysbindin epistatic interaction.
- Author
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Papaleo F, Burdick MC, Callicott JH, and Weinberger DR
- Subjects
- Dysbindin, Dystrophin-Associated Proteins, Humans, Magnetic Resonance Imaging, Neuroimaging, Carrier Proteins genetics, Carrier Proteins physiology, Catechol O-Methyltransferase genetics, Catechol O-Methyltransferase physiology, Epistasis, Genetic, Prefrontal Cortex physiology
- Published
- 2014
- Full Text
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17. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways.
- Author
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Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN, and Weinberger DR
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- Action Potentials drug effects, Action Potentials genetics, Amphetamine adverse effects, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Disease Models, Animal, Dopamine Agents pharmacology, Dysbindin, Dystrophin-Associated Proteins, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Hyperkinesis drug therapy, Hyperkinesis etiology, Hyperkinesis genetics, Maze Learning drug effects, Memory Disorders drug therapy, Memory Disorders etiology, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Mice, Inbred DBA, Mice, Knockout, Motor Activity drug effects, Motor Activity genetics, Prefrontal Cortex drug effects, Prefrontal Cortex pathology, Pyramidal Cells drug effects, Reaction Time drug effects, Reaction Time genetics, Schizophrenia complications, Sensory Gating drug effects, Sensory Gating genetics, Stress, Psychological physiopathology, Carrier Proteins genetics, Dopamine metabolism, Prefrontal Cortex physiopathology, Receptors, Dopamine D2 metabolism, Schizophrenia pathology
- Abstract
Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/- were also respectively more and less sensitive to D2 agonist- and antagonist-induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and CaMKKβ in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis.
- Published
- 2012
- Full Text
- View/download PDF
18. GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.
- Author
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Chen X, Lee G, Maher BS, Fanous AH, Chen J, Zhao Z, Guo A, van den Oord E, Sullivan PF, Shi J, Levinson DF, Gejman PV, Sanders A, Duan J, Owen MJ, Craddock NJ, O'Donovan MC, Blackman J, Lewis D, Kirov GK, Qin W, Schwab S, Wildenauer D, Chowdari K, Nimgaonkar V, Straub RE, Weinberger DR, O'Neill FA, Walsh D, Bronstein M, Darvasi A, Lencz T, Malhotra AK, Rujescu D, Giegling I, Werge T, Hansen T, Ingason A, Nöethen MM, Rietschel M, Cichon S, Djurovic S, Andreassen OA, Cantor RM, Ophoff R, Corvin A, Morris DW, Gill M, Pato CN, Pato MT, Macedo A, Gurling HM, McQuillin A, Pimm J, Hultman C, Lichtenstein P, Sklar P, Purcell SM, Scolnick E, St Clair D, Blackwood DH, and Kendler KS
- Subjects
- Black or African American genetics, Carrier Proteins genetics, Case-Control Studies, Data Mining, Dysbindin, Dystrophin-Associated Proteins, Germany epidemiology, Germany ethnology, Humans, Ireland epidemiology, Jews genetics, Linkage Disequilibrium, Pennsylvania epidemiology, Risk, Schizophrenia epidemiology, Schizophrenia ethnology, White People genetics, Genome-Wide Association Study, Muscle Proteins genetics, Polymorphism, Single Nucleotide, Schizophrenia genetics
- Abstract
We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
- Published
- 2011
- Full Text
- View/download PDF
19. Dysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53.
- Author
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Ma X, Fei E, Fu C, Ren H, and Wang G
- Subjects
- Animals, Carrier Proteins genetics, Cells, Cultured metabolism, Cells, Cultured ultrastructure, Cerebral Cortex cytology, Cytoplasm metabolism, Dysbindin, Dystrophin-Associated Proteins, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Neurologic Mutants, Microfilament Proteins metabolism, Nerve Tissue Proteins, Neurons metabolism, Nuclear Proteins, RNA Interference, RNA, Small Interfering pharmacology, Rats, Rats, Sprague-Dawley, Specific Pathogen-Free Organisms, Two-Hybrid System Techniques, rab GTP-Binding Proteins metabolism, Carrier Proteins physiology, Neurites physiology, Transcription, Genetic physiology, Tumor Suppressor Protein p53 physiology
- Abstract
Genetic variations in the DTNBP1 gene (encoding the protein dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. Previous studies have indicated that dysbindin-1 functions in the regulation of synaptic activity. Recently, dysbindin-1 has also been documented to be involved in neuronal development. In this study, we identified necdin as a binding partner of dysbindin-1 using a yeast two-hybrid screen. Dysbindin-1 recruits necdin to the cytoplasm, thereby attenuating the repressive effects of necdin on p53 transcriptional activity. Knockdown of dysbindin-1, like knockdown of p53, greatly decreases the expressions of the p53 target genes coronin 1b and rab13, which are required for neurite outgrowth. Moreover, overexpression of p53 restores the neurite outgrowth blocked by dysbindin-1 knockdown. In brains of dysbindin-1 null mice (the sandy strain), p21, Coronin 1b and Rab13 levels are reduced. Furthermore, primary cultured cortical neurons from sandy mice display neurite outgrowth defects when compared with those from wild-type mice. Thus, our data provide evidence that dysbindin-1 has an important role in neurite outgrowth through its regulation of p53's transcriptional activity.
- Published
- 2011
- Full Text
- View/download PDF
20. Dysbindin-1 genotype effects on emotional working memory.
- Author
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Wolf C, Jackson MC, Kissling C, Thome J, and Linden DE
- Subjects
- Adult, Brain blood supply, Chi-Square Distribution, Dysbindin, Dystrophin-Associated Proteins, Face, Female, Functional Laterality, Gene Frequency genetics, Genotype, Humans, Image Processing, Computer-Assisted, Linear Models, Magnetic Resonance Imaging methods, Male, Middle Aged, Neuropsychological Tests, Oxygen blood, Pattern Recognition, Visual physiology, Photic Stimulation methods, Recognition, Psychology, Young Adult, Brain physiology, Brain Mapping, Carrier Proteins genetics, Emotions physiology, Memory, Short-Term physiology, Polymorphism, Single Nucleotide genetics
- Abstract
We combined functional imaging and genetics to investigate the behavioral and neural effects of a dysbindin-1 (DTNBP1) genotype associated with the expression level of this important synaptic protein, which has been implicated in schizophrenia. On a working memory (WM) task for emotional faces, participants with the genotype related to increased expression showed higher WM capacity for happy faces compared with the genotype related to lower expression. Activity in several task-related brain areas with known DTNBP1 expression was increased, including hippocampal, temporal and frontal cortex. Although these increases occurred across emotions, they were mostly observed in areas whose activity correlated with performance for happy faces. This suggests effects of variability in DTNBP1 on emotion-specific WM capacity and region-specific task-related brain activation in humans. Synaptic effects of DTNBP1 implicate that altered dopaminergic and/or glutamatergic neurotransmission may be related to the increased WM capacity. The combination of imaging and genetics thus allows us to bridge the gap between the cellular/molecular and systems/behavioral level and extend the cognitive neuroscience approach to a comprehensive biology of cognition.
- Published
- 2011
- Full Text
- View/download PDF
21. Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation.
- Author
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Ito H, Morishita R, Shinoda T, Iwamoto I, Sudo K, Okamoto K, and Nagata K
- Subjects
- Adaptor Proteins, Signal Transducing, Age Factors, Animals, Blotting, Western, Carrier Proteins genetics, Cells, Cultured, Dysbindin, Dystrophin-Associated Proteins, Hippocampus cytology, Hippocampus embryology, Hippocampus growth & development, Nerve Tissue Proteins genetics, Neurons cytology, Neurons metabolism, Neurons ultrastructure, RNA, Small Interfering, Rats, Schizophrenia physiopathology, Synapses metabolism, Wiskott-Aldrich Syndrome Protein, Neuronal metabolism, Carrier Proteins metabolism, Dendritic Spines metabolism, Multiprotein Complexes metabolism, Nerve Tissue Proteins metabolism, Schizophrenia metabolism, Wiskott-Aldrich Syndrome Protein Family metabolism
- Abstract
Genetic variations in dysbindin-1 (dystrobrevin-binding protein-1) are one of the most commonly reported variations associated with schizophrenia. As schizophrenia could be regarded as a neurodevelopmental disorder resulting from abnormalities of synaptic connectivity, we attempted to clarify the function of dysbindin-1 in neuronal development. We examined the developmental change of dysbindin-1 in rat brain by western blotting and found that a 50 kDa isoform is highly expressed during the embryonic stage, whereas a 40 kDa one is detected at postnatal day 11 and increased thereafter. Immunofluorescent analyses revealed that dysbindin-1 is enriched at the spine-like structure of primary cultured rat hippocampal neurons. We identified WAVE2, but not N-WASP, as a binding partner for dysbindin-1. We also found that Abi-1, a binding molecule for WAVE2 involved in spine morphogenesis, interacts with dysbindin-1. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. RNA interference-mediated knockdown of dysbindin-1 led to the generation of abnormally elongated immature dendritic protrusions. The present results indicate possible functions of dysbindin-1 at the postsynapse in the regulation of dendritic spine morphogenesis through the interaction with WAVE2 and Abi-1.
- Published
- 2010
- Full Text
- View/download PDF
22. The dystrobrevin-binding protein 1 gene: features and networks.
- Author
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Guo AY, Sun J, Riley BP, Thiselton DL, Kendler KS, and Zhao Z
- Subjects
- Animals, Dysbindin, Dystrophin-Associated Proteins, Humans, Carrier Proteins genetics, Carrier Proteins metabolism, Evolution, Molecular, Polymorphism, Single Nucleotide genetics
- Abstract
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.
- Published
- 2009
- Full Text
- View/download PDF
23. New genes associated with schizophrenia in neurite formation: a review of cell culture experiments.
- Author
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Bellon A
- Subjects
- Animals, Cells, Cultured, Central Nervous System growth & development, Central Nervous System metabolism, Dysbindin, Dystrophin-Associated Proteins, Humans, Neural Pathways growth & development, Neural Pathways metabolism, Carrier Proteins metabolism, Nerve Tissue Proteins metabolism, Neuregulin-1 metabolism, Neurites metabolism, Proto-Oncogene Proteins c-akt metabolism, Schizophrenia metabolism
- Abstract
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.
- Published
- 2007
- Full Text
- View/download PDF
24. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.
- Author
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Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, and Brandon NJ
- Subjects
- Biological Transport physiology, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Division physiology, Cognition physiology, Cytoskeleton metabolism, Dysbindin, Dystrophin-Associated Proteins, Humans, Risk Factors, Schizophrenia epidemiology, Two-Hybrid System Techniques, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Schizophrenia genetics, Schizophrenia physiopathology, Synapses physiology
- Abstract
Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
- Published
- 2007
- Full Text
- View/download PDF
25. Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations.
- Author
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Li T, Zhang F, Liu X, Sun X, Sham PC, Crombie C, Ma X, Wang Q, Meng H, Deng W, Yates P, Hu X, Walker N, Murray RM, St Clair D, and Collier DA
- Subjects
- Alleles, Case-Control Studies, China, Chromosomes, Human, Pair 6 genetics, Dysbindin, Dystrophin-Associated Proteins, Female, Genetic Markers, Haplotypes, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Risk Factors, Scotland, Carrier Proteins genetics, Schizophrenia genetics
- Abstract
The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.
- Published
- 2005
- Full Text
- View/download PDF
26. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
- Author
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Harrison PJ and Weinberger DR
- Subjects
- Brain pathology, Carrier Proteins genetics, Dysbindin, Dystrophin-Associated Proteins, Gene Expression Regulation, Humans, Neuregulin-1 genetics, Schizophrenia pathology, Schizophrenia physiopathology, Brain physiopathology, Catechol O-Methyltransferase genetics, Genetic Predisposition to Disease genetics, Schizophrenia genetics
- Abstract
This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
- Published
- 2005
- Full Text
- View/download PDF
27. Family-based association study of DTNBP1 in 6p22.3 and schizophrenia.
- Author
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Tang JX, Zhou J, Fan JB, Li XW, Shi YY, Gu NF, Feng GY, Xing YL, Shi JG, and He L
- Subjects
- Adult, Dysbindin, Dystrophin-Associated Proteins, Family Health, Female, Humans, Male, Carrier Proteins genetics, Chromosomes, Human, Pair 6, Schizophrenia genetics
- Published
- 2003
- Full Text
- View/download PDF
28. Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.
- Author
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van den Oord EJ, Sullivan PF, Jiang Y, Walsh D, O'Neill FA, Kendler KS, and Riley BP
- Subjects
- Dysbindin, Dystrophin-Associated Proteins, Evolution, Molecular, Genetic Markers, Genetic Predisposition to Disease epidemiology, Haplotypes, Humans, Ireland epidemiology, Linkage Disequilibrium, Northern Ireland epidemiology, Phylogeny, Polymorphism, Single Nucleotide, Risk Factors, Carrier Proteins genetics, Schizophrenia epidemiology, Schizophrenia genetics
- Abstract
A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.
- Published
- 2003
- Full Text
- View/download PDF
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