| 1 | Mol. Psychiatry 2003 Jul 8: 685-94 |
|---|---|
| PMID | 12874605 |
| Title | Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with schizophrenia in a Scottish family. Predicted DISC1 product has no significant homology to other known proteins. Here, we demonstrated the existence of DISC1 protein and identified fasciculation and elongation protein zeta-1 (FEZ1) as an interacting partner of DISC1 by a yeast two-hybrid study. FEZ1 and its nematode homolog are reported to represent a new protein family involved in axonal outgrowth and fasciculation. In cultured hippocampal neurons, DISC1 and FEZ1 colocalized in growth cones. Interactions of these proteins were associated with F-actin. In the course of neuronal differentiation of PC12 cells, upregulation of DISC1/FEZ1 interaction was observed as along with enhanced extension of neurites by overexpression of DISC1. The present study shows that DISC1 participates in neurite outgrowth through its interaction with FEZ1. Recent studies have provided reliable evidence that schizophrenia is a neurodevelopmental disorder. As there is a high level of DISC1 expression in developing rat brain, dysfunction of DISC1 may confer susceptibility to psychiatric illnesses through abnormal development of the nervous system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Brain Res. Mol. Brain Res. 2004 Mar 122: 89-92 |
| PMID | 14992819 |
| Title | Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. |
| Abstract | Fasciculation and elongation protein zeta-1 (FEZ1) is a mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth and fasciculation. Recently, we reported that FEZ1 interacts with Disrupted-In-schizophrenia 1 (DISC1), a product of the candidate gene for schizophrenia, and that the interaction between these proteins has a role in neurite outgrowth. This time, we investigated the expression of FEZ1 and DISC1 in the developing rat brain using in situ hybridization. Both FEZ1 and DISC1 showed high levels of expression, especially in developing hippocampal neurons. These findings suggest the potential involvement of FEZ1 and DISC1 in the formation of hippocampal neural circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Biol. Psychiatry 2004 Nov 56: 683-90 |
| PMID | 15522253 |
| Title | Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. |
| Abstract | DISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts. We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing. The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396Tschizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder. A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Biol. Psychiatry 2004 Nov 56: 683-90 |
| PMID | 15522253 |
| Title | Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. |
| Abstract | DISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts. We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing. The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396Tschizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder. A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Mol. Cell. Neurosci. 2005 Apr 28: 613-24 |
| PMID | 15797709 |
| Title | Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central coiled-coil region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Hum. Mol. Genet. 2006 Apr 15: 1245-58 |
| PMID | 16510495 |
| Title | Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. |
| Abstract | DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Dialogues Clin Neurosci 2006 -1 8: 353-7 |
| PMID | 17117617 |
| Title | Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia. |
| Abstract | The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Dialogues Clin Neurosci 2006 -1 8: 353-7 |
| PMID | 17117617 |
| Title | Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia. |
| Abstract | The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Neurosci. Lett. 2007 May 417: 316-21 |
| PMID | 17346882 |
| Title | Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Curr. Opin. Neurobiol. 2007 Feb 17: 95-102 |
| PMID | 17258902 |
| Title | Role of DISC1 in neural development and schizophrenia. |
| Abstract | How can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Curr. Opin. Neurobiol. 2007 Feb 17: 95-102 |
| PMID | 17258902 |
| Title | Role of DISC1 in neural development and schizophrenia. |
| Abstract | How can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Neurosci. Lett. 2007 May 417: 326-9 |
| PMID | 17374448 |
| Title | Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population. |
| Abstract | Fasciculation and elongation of protein zeta-1 (FEZ1) is a binding partner of Disrupted-In-schizophrenia 1 (DISC1). Because the DISC1 gene is shown to be a causative gene for psychosis in a Scottish family, the FEZ1 gene may well have importance in mental disease. A previous association study that analyzed polymorphisms of the FEZ1 gene in Japanese patients with schizophrenia and control subjects found significant association of the Asp123Glu polymorphism with schizophrenia. In the present study, we examined two polymorphic markers, rs559668 and rs597570 (Asp123Glu), in the FEZ1 gene to confirm the association in 1920 Japanese patients with schizophrenia and 1920 control subjects. The power to detect an association was more than 0.98. However, we did not detect genotypic associations of either of these two single nucleotide polymorphisms with schizophrenia (p=1 and 0.79, respectively). We concluded that the missense mutation Asp123Glu of the FEZ1 gene is unlikely to play a substantial role in the genetic susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Neuropsychopharmacology 2007 Jan 32: 190-6 |
| PMID | 16936715 |
| Title | The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. |
| Abstract | schizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Neuropsychopharmacology 2007 Jan 32: 190-6 |
| PMID | 16936715 |
| Title | The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. |
| Abstract | schizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Hum. Mol. Genet. 2008 Oct 17: 3191-203 |
| PMID | 18647754 |
| Title | Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. |
| Abstract | FEZ1 (fasciculation and elongation protein zeta 1), a mammalian ortholog of Caenorhabditis elegans UNC-76, interacts with DISC1 (disrupted in schizophrenia 1), a schizophrenia susceptibility gene product, and polymorphisms of human FEZ1 have been associated with schizophrenia. We have now investigated the role of FEZ1 in brain development and the pathogenesis of schizophrenia by generating mice that lack FEZ1. Immunofluorescence staining revealed FEZ1 to be located predominantly in gamma-aminobutyric acid-containing interneurons. The FEZ1(-/-) mice showed marked hyperactivity in a variety of behavioral tests as well as enhanced behavioral responses to the psychostimulants MK-801 and methamphetamine. In vivo microdialysis revealed that the methamphetamine-induced release of dopamine in the nucleus accumbens was exaggerated in the mutant mice, suggesting that enhanced mesolimbic dopaminergic transmission contributes to their hyperactivity phenotype. These observations implicate impairment of FEZ1 function in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Brain Struct Funct 2008 Sep 213: 255-71 |
| PMID | 18470533 |
| Title | Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. |
| Abstract | The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected] |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Schizophr. Res. 2009 Oct 114: 39-49 |
| PMID | 19632097 |
| Title | Genetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia. |
| Abstract | Convergent evidence from genetic linkage, genetic association and biological studies implicates the Disrupted in schizophrenia 1 (DISC1) gene in the etiology and pathophysiology of schizophrenia. We conducted genetic association studies in matched case-control and family sample sets (N=117 families; N=210 case-control pairs), testing polymorphisms across DISC1 and DISC1 interacting genes: LIS1, NUDEL, FEZ1 and PDE4B. We found that DISC1 variants, particularly in the exon 9/intron 9/intron 10 region of the gene, may be associated with risk for schizophrenia in our sample population. There was no strong evidence for association with LIS1, NUDEL, FEZ1 and PDE4B. Gene-gene interaction analyses and mRNA quantification in post-mortem brains from schizophrenia patients and control subjects did not reveal significant differences. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Hum. Genet. 2010 Apr 127: 441-52 |
| PMID | 20084519 |
| Title | Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging. |
| Abstract | The etiology of schizophrenia likely involves genetic interactions. DISC1, a promising candidate susceptibility gene, encodes a protein which interacts with many other proteins, including CIT, NDEL1, NDE1, FEZ1 and PAFAH1B1, some of which also have been associated with psychosis. We tested for epistasis between these genes in a schizophrenia case-control study using machine learning algorithms (MLAs: random forest, generalized boosted regression andMonteCarlo logic regression). Convergence of MLAs revealed a subset of seven SNPs that were subjected to 2-SNP interaction modeling using likelihood ratio tests for nested unconditional logistic regression models. Of the 7C2 = 21 interactions, four were significant at the ? = 0.05 level: DISC1 rs1411771-CIT rs10744743 OR = 3.07 (1.37, 6.98) p = 0.007; CIT rs3847960-CIT rs203332 OR = 2.90 (1.45, 5.79) p = 0.003; CIT rs3847960-CIT rs440299 OR = 2.16 (1.04, 4.46) p = 0.038; one survived Bonferroni correction (NDEL1 rs4791707-CIT rs10744743 OR = 4.44 (2.22, 8.88) p = 0.00013). Three of four interactions were validated via functional magnetic resonance imaging (fMRI) in an independent sample of healthy controls; risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during the N-back task, a schizophrenia-linked intermediate biological phenotype: rs3847960-rs440299; rs1411771-rs10744743, rs4791707-rs10744743 (SPM5 p < 0.05, corrected), although we were unable to statistically replicate the interactions in other clinical samples. Interestingly, the CIT SNPs are proximal to exons that encode theDISC1 interaction domain. In addition, the 3' UTR DISC1 rs1411771 is predicted to be an exonic splicing enhancer and the NDEL1 SNP is ~3,000 bp from the exon encoding the region of NDEL1 that interacts with the DISC1 protein, giving a plausible biological basis for epistasis signals validated by fMRI. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | PLoS ONE 2011 -1 6: e23450 |
| PMID | 21853134 |
| Title | Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population. |
| Abstract | In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Neuron 2011 Nov 72: 559-71 |
| PMID | 22099459 |
| Title | Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. |
| Abstract | Disrupted-in schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Neurosci. Res. 2011 Sep 71: 71-7 |
| PMID | 21664390 |
| Title | DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses, including bipolar disorder and schizophrenia. Although the roles of DISC1 in nervous system development and functions are increasingly recognized, pathophysiological mechanisms underlying a range of neuropsychiatric symptoms caused by DISC1 mutations remain unclear. Here we show that DISC1 enhances synaptic vesicle transport along microtubules. Knocking down DISC1 expression results in attenuated vesicle transport in primary cortical neurons. Likewise, expressing the dominant-negative, breakpoint mutant version of DISC1 causes defective vesicle transport, by disrupting the assembly between the kinesin-1 adaptor FEZ1 and the cargo protein Synaptotagmin-1 (Syt-1). In addition, lithium, a mood-stabilizing agent used for the treatment of bipolar disorder, can restore the assembly of FEZ1 and Syt-1, and normalizes the defective transport caused by the dominant-negative DISC1. Thus, this study addresses a new role of DISC1 in organelle transport in neurons, and suggests that this cellular pathway could be therapeutically targeted for the treatment against neuropsychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Transl Psychiatry 2011 -1 1: e30 |
| PMID | 22832604 |
| Title | Interactions of human truncated DISC1 proteins: implications for schizophrenia. |
| Abstract | Numerous genetic linkage and association reports have implicated the Disrupted-in-schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3? and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants L?78, L?3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3?. The temporal expression pattern of GSK3? in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Cell Rep 2014 Apr 7: 552-64 |
| PMID | 24726361 |
| Title | Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system. |
| Abstract | Downregulation of the schizophrenia-associated gene DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Biomed Rep 2014 Sep 2: 729-736 |
| PMID | 25054019 |
| Title | Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | PLoS ONE 2014 -1 9: e99892 |
| PMID | 24940743 |
| Title | Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia. |
| Abstract | Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | PLoS ONE 2014 -1 9: e99892 |
| PMID | 24940743 |
| Title | Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia. |
| Abstract | Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Mol Neuropsychiatry 2015 Oct 1: 175-190 |
| PMID | 27239468 |
| Title | Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness. |
| Abstract | Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Anat Sci Int 2015 Jun 90: 137-43 |
| PMID | 25595671 |
| Title | Molecular basis of major psychiatric diseases such as schizophrenia and depression. |
| Abstract | Recently several potential susceptibility genes for major psychiatric disorders (schizophrenia and major depression) such as disrupted-in-schizophrenia 1(DISC1), dysbindin and pituitary adenylate cyclase-activating polypeptide (PACAP) have been reported. DISC1 is involved in neural development directly via adhesion molecules or via its binding partners of DISC1 such as elongation protein ?-1 (FEZ1), DISC1-binding zinc-finger protein (DBZ) and kendrin. PACAP also regulates neural development via stathmin 1 or via regulation of the DISC1-DBZ binding. Dysbindin is also involved in neural development by regulating centrosomal microtubule network formation. All such molecules examined to date are involved in neural development. Thus, these findings provide new molecular insights into the mechanisms of neural development and neuropsychiatric disorders. On the other hand, in addition to neurons, both DISC and DBZ have been detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 inhibits the differentiation of oligodendrocyte precursor cells into oligodendrocytes, while DBZ has a positive regulatory role in oligodendrocyte differentiation. Evidence suggesting that disturbance of oligodendrocyte development causes major depression is also described. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Balkan J. Med. Genet. 2015 Jun 18: 31-8 |
| PMID | 26929903 |
| Title | Investigation of fasciculation and elongation protein ?-1 (FEZ1) in peripheral blood reveals differences in gene expression in patients with schizophrenia. |
| Abstract | schizophrenia (SZ) is a chronic neuropsychiatric disorder characterized by affective, neuromorphological and cognitive impairment, deteriorated social functioning and psychosis with underlying molecular abnormalities, including gene expression changes. Observations have suggested that fasciculation and elongation protein ?-1 (FEZ1) may be implicated in the pathogenesis of schizophrenia. Nevertheless, our current knowledge of the expression of FEZ1 in peripheral blood of schizophrenia patients remains unclear. The purpose of this study was to identify the characteristic gene expression patterns of FEZ1 in peripheral blood samples from schizophrenia patients. We performed quantitative reverse-transcriptase (qRT-PCR) analysis using peripheral blood from drug-free schizophrenia patients (n = 29) and age and gender-matched general population controls (n = 24). For the identification of FEZ1 gene expression patterns, we applied a comparative threshold cycle (CT) method. A statistically significant difference of FEZ1 mRNA level was revealed in schizophrenia subjects compared to healthy controls (p = 0.0034). To the best of our knowledge, this study is the first describing a down-regulation of FEZ1 gene expression in peripheral blood of patients with schizophrenia. Our results suggested a possible functional role of FEZ1 in the pathogenesis of schizophrenia and confirmed the utility of peripheral blood samples for molecular profiling of psychiatric disorders including schizophrenia. The current study describes FEZ1 gene expression changes in peripheral blood of patients with schizophrenia with significantly down-regulation of FEZ1 mRNA. Thus, our results provide support for a model of SZ pathogenesis that includes the effects of FEZ1 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |