DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness

@article{Millar2004DISC1AD,
  title={DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness},
  author={J. Millar and R. James and N. Brandon and P. Thomson},
  journal={Annals of Medicine},
  year={2004},
  volume={36},
  pages={367 - 378}
}
A balanced (1;11)(q42;q14) translocation co‐segregates with schizophrenia and major affective disorders in a large Scottish family. The translocation breakpoint on chromosome 1 is located within the Disrupted in Schizophrenia 1 and 2 genes (DISC1 and DISC2). Consequently loss of normal function of these genes is likely to underlie the susceptibility to developing psychiatric disorders that is conferred by inheritance of the translocation. Additionally, a number of independent genetic studies… Expand
The Genetics and Biology of Disc1—An Emerging Role in Psychosis and Cognition
TLDR
The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies that indicate thatDISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. Expand
Schizophrenia in translation: disrupted in schizophrenia (DISC1): integrating clinical and basic findings.
  • R. Roberts
  • Psychology, Medicine
  • Schizophrenia bulletin
  • 2007
TLDR
Converging evidence from cell culture, mice mutants, postmortem brain, and genetics implicates mutant DISC1 in the pathophysiology of schizophrenia and other mental illnesses. Expand
Characterisation of DISC1 ubiquitination and its potential as a therapeutic intervention for psychiatric disorders
TLDR
The work described in this thesis has uncovered 2 novel post translational modifications and identified the E3 ligase involved in regulating DISC1 turn over, which indicates the feasibility of controlled and directed differentiation of patient specific iPS cells in to neurons, which act as a useful tool for disease modelling. Expand
Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population
TLDR
Evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population is reported, consistent with the diagnoses in the original Scottish translocation family. Expand
A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder
TLDR
A 4 bp deletion at the extreme 3′ end of exon 12 in a proband with schizophrenia is detected, consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders. Expand
Genetics of Schizophrenia: The 1q42 Locus in Finnish Families
TLDR
This analysis highlighted four restricted genomic regions that significantly associate with schizophrenia, including a locus containing a DISC1 interacting gene, NDE1, as it highlights the pathway these two genes act along for a role in schizophrenia. Expand
Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia
TLDR
The expression of NUDEL, FEZ1, and LIS1 vas significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms, suggesting involvement of genetically linked abnormalities in the DISC 1 molecular pathway in the pathophysiology of schizophrenia. Expand
Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs.
TLDR
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, which implicate genetically linked abnormalities in the DISC 1 molecular pathway in the pathophysiology of schizophrenia. Expand
Neurogenetics: insights into degenerative diseases and approaches to schizophrenia
TLDR
Determining the cellular localization, protein partners, and function of the normal and mutated DISC1 protein may provide important insights into the more common forms of major mental illness. Expand
Animal model for schizophrenia that reflects gene-environment interactions.
TLDR
It is shown how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 59 REFERENCES
Disruption of two novel genes by a translocation co-segregating with schizophrenia.
TLDR
Observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness. Expand
Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia
TLDR
A contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region has provided the basis for examination of the genomic structure of DISC1, a candidate gene potentially involved in the aetiology of major psychiatric illness. Expand
Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria
TLDR
Of the many cellular functions performed by mitochondria, their role in oxidative phosphorylation, calcium homeostasis, and apoptosis may hold particular relevance for the neuronal disturbances believed to be involved in the pathogenesis of schizophrenia. Expand
Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family.
TLDR
The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders. Expand
Do schizophrenia and affective disorder share susceptibility genes?
TLDR
Findings imply shared loci for schizophrenia and affective disorders among those required for the full expression of the phenotype, and identification and molecular characterization of the genetic components conferring risk to both disorders would impact positively on diagnosis, prevention, and treatment. Expand
Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
TLDR
It is demonstrated that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel and is able to act as a bridge between DISC 1 and Lis1 to allow formation of a trimolecular complex. Expand
DISC1 (Disrupted in Schizophrenia‐1) is expressed in limbic regions of the primate brain
TLDR
Disrupted in Schizophrenia‐1 expression is highly localized, with most prominent expression in the dentate gyrus of the hippocampus and lateral septum, and lower levels ofexpression in the cerebral cortex, amygdala, paraventricular hypothalamus, cerebellum, interpeduncular nucleus, and subthalamic nucleus. Expand
Evolutionary constraints on the Disrupted in Schizophrenia locus.
TLDR
The amino acid sequence of DISC1 is diverging rapidly, although a putative nuclear localization signal and discrete blocks of coiled coil are specifically conserved features. Expand
Identification of genes from a schizophrenia-linked translocation breakpoint region.
TLDR
A BAC clone contig encompassing 2.51 Mb around the chromosome 11 breakpoint, which was constructed computationally using draft genomic sequence data and existing mapping data for the region, has led to the identification and relative ordering of 10 candidate genes in the area, including 2 novel transcripts. Expand
Association within a family of a balanced autosomal translocation with major mental illness
TLDR
The findings suggest that the q21-22 region of chromosome 11 may be a promising area to examine for genes predisposing to major mental illness. Expand
...
1
2
3
4
5
...