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Molecular psychiatry 03/2011; 16(7):693-4. · 15.05 Impact Factor
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S M Brown,
S J Clapcote, J K Millar,
H S Torrance,
S M Anderson,
R Walker,
A Rampino,
J C Roder,
P A Thomson,
D J Porteous,
K L Evans
Molecular psychiatry 02/2011; 16(6):585-7. · 15.05 Impact Factor
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ABSTRACT: The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention.
Molecular Psychiatry 02/2008; 13(1):36-64. · 13.67 Impact Factor
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K Ishizuka,
J Chen,
S Taya,
W Li, J K Millar,
Y Xu,
S J Clapcote,
C Hookway,
M Morita,
A Kamiya, [......],
B K Lipska,
J C Roder,
M Pletnikov,
D Porteous,
A J Silva,
T D Cannon,
K Kaibuchi,
N J Brandon,
D R Weinberger,
A Sawa
Molecular Psychiatry 11/2007; 12(10):897-9. · 13.67 Impact Factor
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ABSTRACT: The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative sample of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of individual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.
Molecular Psychiatry 07/2005; 10(7):657-68, 616. · 13.67 Impact Factor
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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.
Molecular and Cellular Neuroscience 05/2005; 28(4):613-24. · 3.66 Impact Factor
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ABSTRACT: The disruption of genes by balanced translocations and other rare germline chromosomal abnormalities has played an important part in the discovery of many common Mendelian disorder genes, somatic oncogenes and tumour supressors. A search of published literature has identified 15 genes whose genomic sequences are directly disrupted by translocation breakpoints in individuals with neuropsychiatric illness. In these cases, it is reasonable to hypothesise that haploinsufficiency is a major factor contributing to illness. These findings suggest that the predicted polygenic nature of psychiatric illness may not represent the complete picture; genes of large individual effect appear to exist. Cytogenetic events may provide important insights into neurochemical pathways and cellular processes critical for the development of complex psychiatric phenotypes in the population at large.
The Pharmacogenomics Journal 02/2005; 5(2):81-8. · 4.54 Impact Factor
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ABSTRACT: In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.
Molecular Psychiatry 12/2004; 9(12):1083-90. · 13.67 Impact Factor
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ABSTRACT: DISC1 is disrupted by a chromosomal translocation cosegregating with schizophrenia and recurrent major depression in a large Scottish family and has also been reported as a potential susceptibility locus in independent populations. We reveal a widespread and complex pattern of DISC1 expression, with at least five forms of Disrupted in Schizophrenia 1 DISC1 detectable. Mitochondria are the predominant site of DISC1 expression with additional nuclear, cytoplasmic, and actin-associated locations evident. Although the subcellular targeting of DISC1 is clearly complex, the association with mitochondria is of interest as many mitochondrial deficits have been reported in schizophrenia and other neuropsychiatric illnesses. Moreover, 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.
Molecular and Cellular Neuroscience 06/2004; 26(1):112-22. · 3.66 Impact Factor
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D J Porteous,
K L Evans, J K Millar,
B S Pickard,
P A Thomson,
R James,
S MacGregor,
N R Wray,
P M Visscher,
W J Muir,
D H Blackwood
Cold Spring Harbor Symposia on Quantitative Biology 02/2003; 68:383-94.
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R S Devon,
S Anderson,
P W Teague,
P Burgess,
T M Kipari,
C A Semple, J K Millar,
W J Muir,
V Murray,
A J Pelosi,
D H Blackwood,
D J Porteous
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ABSTRACT: We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.
Psychiatric Genetics 07/2001; 11(2):71-8. · 2.58 Impact Factor
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ABSTRACT: Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.
Molecular Psychiatry 04/2001; 6(2):173-8. · 13.67 Impact Factor
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ABSTRACT: Two candidate genes, DISC1 and DISC2 on chromosome 1, are disrupted by a translocation that segregates with major psychiatric illness. Several DISC1 transcripts contain TRAX (HGMW-approved symbol TSNAX) sequence at the 5' end. These transcripts initiate at the 5' end of TRAX and terminate at the final exon of DISC1. Five species of transcript resulting from intergenic splicing have been identified; one encodes a novel TRAX/DISC1 fusion protein. The remaining four transcripts are bicistronic and encode a series of novel truncated isoforms of TRAX and DISC1. Demonstration that the various TRAX/DISC1 transcripts are translated awaits further experimentation. As a consequence of the observation of intergenic splicing, the human TRAX gene has been mapped at least 35 kb proximal to DISC1 and within approximately 150-250 kb of the translocation breakpoint at 1q42.1. The TRAX gene consists of six exons with a putative CpG island at the 5' end. Four major transcripts are produced from this gene, of which the smallest, at 2.7 kb, had previously been identified.
Genomics 08/2000; 67(1):69-77. · 3.02 Impact Factor
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J K Millar,
J C Wilson-Annan,
S Anderson,
S Christie,
M S Taylor,
C A Semple,
R S Devon,
D M St Clair,
W J Muir,
D H Blackwood,
D J Porteous
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ABSTRACT: A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
Human Molecular Genetics 06/2000; 9(9):1415-23. · 7.64 Impact Factor
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Mammalian Genome 06/2000; 11(5):395-8. · 2.89 Impact Factor
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J K Millar,
J Brown,
J C Maule,
Y Shibasaki,
S Christie,
D Lawson,
S Anderson,
J C Wilson-Annan,
R S Devon,
D M St Clair,
D H Blackwood,
W J Muir,
D J Porteous
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ABSTRACT: A balanced t(1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related mental illness in a single large Scottish pedigree. We have constructed a long-range restriction map covering at least 3 Mb of the chromosome 11 breakpoint region and conducted searches for genes whose expression could be altered by the translocation, resulting in schizophrenia. Novel transcribed sequences of unknown function clustered around putative CpG islands, located approximately 500 kb and 700 kb above the breakpoint, represent the only evidence to date for expressed genes within the mapped region.
Psychiatric Genetics 02/1998; 8(3):175-81. · 2.58 Impact Factor
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ABSTRACT: We report a case control association study using polymorphic markers D1S1621 and D11S931 in unrelated individuals with schizophrenia, unipolar depression and a matched control group. The two polymorphic markers were identified during the positional cloning of the translocation breakpoint t(1:11)(q43:q14.3) that cosegregates with schizophrenia and affective disorders. These markers provided an opportunity to investigate linkage disequilibrium with a postulated schizophrenia susceptibility gene close to the translocation breakpoint in random populations of schizophrenia and unipolar depression individuals compared with a normal control population. No significant differences between allele frequencies for either of the markers in the affected populations were observed in comparison with the control group, which provides evidence against a nearby gene of major effect in the populations studied.
Psychiatric Genetics 02/1997; 7(4):171-4. · 2.58 Impact Factor
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ABSTRACT: Four distinct DNA ligase activities (I-IV) have been identified within mammalian cells. Evidence has indicated that DNA ligase I is central to DNA replication, as well as being involved in DNA repair processes. A patient with altered DNA ligase I displayed a phenotype similar to Bloom's syndrome, being immunodeficient, growth retarded and predisposed to cancer. Fibroblasts isolated from this patient (46BR) exhibited abnormal lagging strand synthesis and repair deficiency. It has been reported that DNA ligase I is essential for cell viability, but here we show that cells lacking DNA ligase I are in fact viable. Using gene targeting in embryonic stem (ES) cells, we have produced DNA ligase I-deficient mice. Embryos develop normally to mid-term when haematopoiesis usually switches to the fetal liver. Thereupon acute anaemia develops, despite the presence of erythroid-committed progenitor cells in the liver. Thus DNA ligase I is required for normal development, but is not essential for replication. Hence a previously unsuspected redundancy must exist between mammalian DNA ligases.
Nature Genetics 09/1996; 13(4):489-91. · 35.53 Impact Factor
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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.
Molecular and Cellular Neuroscience.
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ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology.
