Disrupted in Schizophrenia 1 (DISC1): Association with Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder

Hodgkinson, Colin A.; Goldman, David; Jaeger, Judith; Persaud, Shalini; Kane, John M.; Lipsky, Robert H.; Malhotra, Anil K.

doi:10.1086/425586

Cited by 397 publications

(263 citation statements)

References 51 publications

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“…13,14 Haplotype analysis with markers in DISC1 suggests an association with bipolar disorder, schizoaffective disorder, and schizophrenia in a collection of American families. 15 The expression pattern and suggested function of DISC1 in neurodevelopment are consistent with a role for DISC1 mutations as risk factors for schizophrenia. DISC1 is expressed in multiple brain regions and in peripheral tissues.…”

supporting

confidence: 52%

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

et al. 2005

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In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3 0 end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders. Molecular Psychiatry (2005) 10, 758-764.

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confidence: 52%

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

et al. 2005

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“…7,8 In addition, a frameshift mutation of DISC1 has been identified in an American family with schizophrenia and schizoaffective disorder, 9 whereas the association of the single-nucleotide polymorphisms of DISC1 with schizophrenia, schizoaffective disorder and bipolar disorder has also been suggested. 10 Although investigating the relationship of DISC1 to susceptibility to psychiatric disorders and brain function, we previously identified fasciculation and elongation protein zeta-1 (FEZ1) 11,12 and Kendrin 13 as DISC1-interacting molecules by yeast two-hybrid screening of a human brain complementary DNA (cDNA) library. DISC1 and FEZ1 were found to be colocalized in growth cones in association with F-actin in both SK-N-SH cells and cultured hippocampal neurons.…”

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confidence: 99%

A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth

et al. 2007

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Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast twohybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C 2 H 2 -type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC 1 ) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.

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“…12 Further evidence for association between bipolar disorder and the DISC1 locus has been shown in a white North American cohort and in the broader Scottish population. 13,14 Other putative susceptibility genes have been implicated in bipolar disorder following their investigation as biological or functional candidate genes. These include BDNF, which showed evidence for association with bipolar disorder in two cohorts of predominantly Caucasian origin, 15,16 although this has not been replicated in several other cohorts of European and Japanese origin.…”

Section: Introductionmentioning

confidence: 99%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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Disrupted in Schizophrenia 1 (DISC1): Association with Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder

Cited by 397 publications

References 51 publications

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

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