| *605210 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DISRUPTED IN SCHIZOPHRENIA 1; DISC1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: DISC1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 1q42.2 Genomic coordinates (GRCh37): 1:231,762,560 - 232,177,017 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Millar et al. (2000) isolated and sequenced a translocation breakpoint region on chromosome 1q42 that had been identified by St. Clair et al. (1990) in a large Scottish family with mental and/or behavioral disorders, including schizophrenia (see 604906), schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. Within the 1q42 chromosomal region, Millar et al. (2000) identified 2 novel genes directly disrupted by the translocation, which the authors termed 'disrupted in schizophrenia' 1 and 2 (DISC1 and DISC2, 606271). The major DISC1 gene is predicted to encode an 854-amino acid protein containing a globular N-terminal domain and a helical C-terminal domain with the potential to form a coiled-coil by interaction with another protein(s). Northern blot analysis identified a 7.5-kb mRNA transcript with ubiquitous expression. DISC2 apparently specifies a single exon thought to be a noncoding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where the antisense RNA may regulate expression of the sense gene. Millar et al. (2000) suggested that DISC1 and DISC2 may confer susceptibility to psychiatric illnesses. Ma et al. (2002) cloned and characterized mouse Disc1, which encodes an 851-amino acid protein that shares 56% sequence identity with the human protein. Both the mouse and human genes show conservation of leucine zipper and coiled-coil domains. In situ hybridization in adult mouse brain showed a restricted expression pattern, with highest levels in the dentate gyrus of the hippocampus and lower expression in CA1-CA3 of the hippocampus, cerebellum, cerebral cortex, and olfactory bulbs. Ozeki et al. (2003) cloned and characterized mouse and rat Disc1. Using Western blot analysis of human brain tissue and cultured human cell lines, Sawamura et al. (2005) found that the DISC1 protein was expressed as 2 distinct bands of 95 to 100 kD and 75 to 85 kD. Subcellular fractionation showed that the 95- to 100-kD isoform was enriched in the cytoplasm, whereas the 75- to 85-kD isoform was present in both the nucleus and cytoplasm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ozeki et al. (2003) demonstrated that rodent Disc1 expression displayed pronounced developmental regulation, with the highest levels in late embryonic life during development of the cerebral cortex. In a yeast 2-hybrid assay of a human whole brain cDNA library, DISC1 interacted with a variety of cytoskeletal proteins. One of these, NUDEL (NDEL1; 607538), is associated with cortical development and is linked to LIS1 (601545). A schizophrenia-associated DISC1 mutant with a C-terminal 257-residue truncation did not bind NUDEL. Expression of mutant DISC1, but not wildtype DISC1, reduced neurite extension in rat adrenal pheochromocytoma cells. Using yeast 2-hybrid, mammalian 2-hybrid, and coimmunoprecipitation assays, Morris et al. (2003) showed that DISC1 interacts with multiple proteins of the centrosome and cytoskeletal system, including MIPT3 (607380), MAP1A (600178), and NUDEL; proteins that localize receptors to membranes, including alpha-actinin-2 (ACTN2; 102573) and beta-4-spectrin (SPTBN4; 606214); and proteins that transduce signals from membrane receptors, including ATF4 (604064) and ATF5 (606398). Truncated mutant DISC1 failed to interact with ATF4, ATF5, or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C terminus of DISC1. In its full-length form, the DISC1 protein localized to predominantly perinuclear punctate structures which extended into neurites in some cells; mutant truncated DISC1, by contrast, was seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms colocalized with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 were found in microtubule fractions, neither form appeared to bind directly to microtubules, but rather did so in a MIPT3-dependent fashion that was stabilized by taxol. Morris et al. (2003) concluded that DISC1 is a multifunctional protein whose truncation may contribute to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture, and/or neuronal migration. Millar et al. (2005) showed that DISC1 interacts with the UCR2 domain of phosphodiesterase-4B (PDE4B; 600127), implicated in susceptibility to schizophrenia, and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and in increase in PDE4B activity. The phosphodiesterases inactivate cAMP, a second messenger implicated in learning, memory, and mood. Millar et al. (2005) proposed a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP. Kamiya et al. (2005) identified Disc1 as a component of the microtubule-associated dynein motor complex in rat PC12 neural precursor cells. Disc1 was essential for maintaining the motor complex at the centrosome. A schizophrenia-associated C-terminally truncated Disc1 mutant functioned in a dominant-negative manner by interacting with and redistributing wildtype Disc1 and by disassociating the Disc1-dynein complex from the centrosome. Depletion of endogenous Disc1 by RNA interference or expression of truncated Disc1 impaired neurite outgrowth in PC12 cells in vitro. In embryonic mice, Disc1 RNA interference led to impaired cerebral cortex development. Kamiya et al. (2005) concluded that loss of normal DISC1 function during cerebral cortex development may underlie neurodevelopmental dysfunction in schizophrenia. Sawamura et al. (2005) analyzed the 75- to 85-kD isoform of DISC1 in postmortem orbitofrontal cortex from 3 groups of 15 individuals with schizophrenia, major depression, and bipolar disorder, respectively, and 15 controls. There was an increased P:S ratio (nuclear pellet:postnuclear supernatant) in schizophrenia and major depression compared to controls; the increase in bipolar disorder did not reach statistical significance. The P:S ratio changes in major depression were significantly influenced by substance/alcohol abuse and by postmortem interval. The alteration in schizophrenic brains was not associated with confounding factors, although an interaction with substance/alcohol abuse could not be ruled out. Burdick et al. (2008) noted that NDE1 (609449) is a homolog of NDEL1 and also binds to DISC1. NDE1 was expressed at constant levels in the rat cerebral cortex from embryonic day (E) 14 to adulthood, whereas NDEL1 expression showed a time-course increase peaking at postnatal day 7. Further studies with a ser704-to-cys (S704C) polymorphism in the DISC1 gene showed that NDE1 bound stronger to ser704, while NDEL1 bound stronger to cys704. The findings suggested an interaction of these 3 proteins, with possible competitive binding between NDEL1 and NDE1 for DISC1. Using knockdown studies, Mao et al. (2009) found that Disc1 was required for neural progenitor cell proliferation in vitro, during embryonic mouse brain development, and in adult mouse dentate gyrus. Disc1 interacted directly with Gsk3-beta (GSK3B; 605004) and inhibited recombinant Gsk3-beta activity in a dose-dependent manner. This inhibition of Gsk3-beta caused reduced phosphorylation and increased stabilization of beta-catenin (CTNNB1; 116806). Knockdown of Disc1 in adult mouse dentate gyrus resulted in hyperactivity and depression-like behaviors. All effects of Disc1 knockdown were reversed by pharmacologic inhibition of Gsk3-beta. Mao et al. (2009) concluded that DISC1 regulates neural progenitor proliferation by modulating GSK3-beta activity and beta-catenin abundance. By immunoprecipitation analysis of cotransfected HEK293 cells, Enomoto et al. (2009) found that mouse Disc1 interacted with girdin (CCDC88A; 609736), a protein required for proper migration and positioning of mouse dentate gyrus cells. Domain mapping revealed that the N-terminal globular domain of Disc1 interacted with the N-terminal domain of girdin. Girdin colocalized with Disc1 in cultured rat hippocampal neurons, and knockdown of Disc1 via small interfering RNA impaired girdin localization at growth cones. Ishizuka et al. (2011) reported that phosphorylation of DISC1 acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signaling via an interaction with GSK3-beta, whereas specific phosphorylation at serine-710 triggers the recruitment of Bardet-Biedl syndrome (see 209900) proteins to the centrosome. In support of this model, loss of BBS1 (209901) leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. Ishizuka et al. (2011) concluded that their data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at serine-710 activates a key developmental switch. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ma et al. (2002) determined that the mouse Disc1 gene maps to chromosome 8 in a region with homology of synteny to human chromosome 1q42. Ma et al. (2002) demonstrated that translin-associated factor X (TSNAX; 602964), which is situated 35 kb proximal to the DISC1 sequence on human chromosome 1, is located approximately 20 kb proximal to Disc1 in the mouse at 69.5 cM. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The family studied by St. Clair et al. (1990) and Millar et al. (2000) was originally ascertained by Jacobs et al. (1970), who reported the translocation in the propositus, who had adolescent conduct disorder, and in members of 4 generations of the extended family. Blackwood et al. (2001) provided a follow-up. Of the 87 members of the family who were karyotyped, 37 carried the (1;11)(q42;q14.3) translocation. A psychiatric diagnosis was reached in 29 carriers, 38 noncarriers, and the 2 founders (who were not karyotyped). The range of symptoms in this family crossed traditional diagnostic boundaries, and the locus identified by the breakpoint on 1q42 appeared to be implicated in either schizophrenia or bipolar disorder (125480). Furthermore, Blackwood (2000) reported abnormalities in the auditory P300 event-related potential, which showed prolonged latency and reduced amplitude in affected members of the family. Ekelund et al. (2001) used a large, population-based study sample (221 Finnish families, 557 affected individuals) to refine the localization of schizophrenia loci on chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. Evidence for linkage was obtained for 1 locus in the combined sample (maximum lod = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (maximum lod = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (maximum lod = 2.30, D1S245). The strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is a marker within DISC1. In a follow-up study to Ekelund et al. (2001), Ekelund et al. (2004) genotyped 300 polymorphic markers on chromosome 1 using a sample of 70 Finnish families with multiple individuals affected with schizophrenia or related conditions. They again found linkage on chromosome 1q42 maximizing within the DISC1 gene (rs1000731, lod of 2.70). By analysis of SNPs and corresponding haplotypes across candidate genes in the 1q42 region identified by Ekelund et al. (2001) as being linked to schizophrenia in a Finnish sample, Hennah et al. (2003) identified a significant region of interest within the DISC1 gene. They identified a 2-SNP haplotype spanning from intron 1 to exon 2 of the DISC1 gene, designated HEP3 (605210.0001), and demonstrated that it was undertransmitted to affected women in the general Finnish population. The HEP3 haplotype also displayed sex differences in transmission distortion, the undertransmission being significant only in affected females. Hodgkinson et al. (2004) presented data from a case-control study of a North American white population, confirming the underrepresentation of the HEP3 haplotype in individuals with schizoaffective disorder. Multiple haplotypes contained within 4 haplotype blocks extending between exon 1 and exon 9 were associated with schizophrenia, schizoaffective disorder, and bipolar disorder. Hodgkinson et al. (2004) also found overrepresentation of a missense allele of the DISC1 gene, leu607 to pro (L607P; rs6675281) in schizoaffective disorder. These data supported the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders. Cannon et al. (2005) conducted a population-based twin cohort study in Finland to examine the association of SNPs of DISC1 and TRAX (TSNAX; 602964) with schizophrenia and several endophenotypic traits thought to be involved in the disease pathogenesis. Two hundred and thirty-six subjects consisting of 7 pairs concordant for schizophrenia (6 monozygotic, 1 dizygotic), 52 pairs discordant for schizophrenia (20 monozygotic, 32 dizygotic), and 59 demographically balanced normal pairs (28 monozygotic, 31 dizygotic) were drawn from a twin cohort consisting of all same-sex twins born in Finland from 1940 through 1957. Diagnosis was confirmed and performance on neurocognitive tests of short- and long-term memory as well as gray matter volume measurements as assessed on MRI images were recorded. A common haplotype incorporating 3 SNPs near the translocation breakpoint of DISC1 (HEP1; odds ratio, 2.6; p = 0.02) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (combined HEP2/HEP3; odds ratio, 13.0; p = 0.001) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative and endophenotypic traits including impairments in short- and long-term memory, functioning, and reduced gray matter density in the prefrontal cortex. Song et al. (2008) analyzed the regions of likely functional significance in the DISC1 gene in 288 patients with schizophrenia and 288 controls. Six patients with schizophrenia were heterozygous for 'ultra-rare' missense variants (R37W, S90L, T603I, G14A, and R418H) not found in 288 controls (p = 0.015) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. Song et al. (2008) concluded that these variants in DISC1 are associated with an attributable risk of about 2% for schizophrenia. In addition, they replicated the finding that 2 common structural variants (Q264R and S704C) slightly elevate the risk for schizophrenia (OR, 1.3, 95% CI, 1.0-1.7). Schumacher et al. (2009) reported a circumscribed interval in intron 9 of DISC1, which was significantly associated with schizophrenia in females (p = 4.0 x 10(-5)) and contributed most strongly to early-onset cases (p = 9.0 x 10(-5)) in a central European population of 1,621 individuals. The SNP interplay effect between rs1538979 and rs821633 significantly conferred disease risk in male patients with schizophrenia (p = 0.016; OR, 1.57). In a metaanalysis of 9 schizophrenia samples from different European populations covering 50 SNPs, the authors found evidence for a common schizophrenia risk interval within DISC1 introns 4 to 6 (p = 0.002; OR, 1.27). Schumacher et al. (2009) proposed a complex association between schizophrenia and DISC1, including the presence of different risk loci and SNP interplay effects. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hikida et al. (2007) developed a transgenic mouse model expressing a dominant-negative truncated form of human DISC1. In vivo brain MRI showed enlarged lateral ventricles particularly on the left side in juvenile mutant mice, similar to asymmetric brain changes observed in patients with schizophrenia. There was also selective reduction of immunoreactivity to parvalbumin (PVALB; 168890) in the cortex, marking a possible interneuron deficit. Mutant mice displayed several behavioral abnormalities, including hyperactivity, disturbances in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit. Hikida et al. (2007) suggested that the dominant-negative human DISC1 transgenic mouse could be an animal model for schizophrenia. Li et al. (2007) used an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of mutant C-terminal DISC1 in mice resulted in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, decreased hippocampal synaptic transmission, depressive-like traits, abnormal spatial working memory, and reduced sociability. Li et al. (2007) postulated that alterations in DISC1 function during brain development may contribute to pathogenesis of schizophrenia. Clapcote et al. (2007) reported the behavioral phenotypes of 2 ENU-induced Disc1 mouse mutants: Q31L and L100P, both in exon 2. All mutant mice were viable and grossly indistinguishable from their wildtype littermates. L110P-mutant mice showed a schizophrenic-like phenotype, with decreased prepulse inhibition and latent inhibition that could be ameliorated by antipsychotic treatment. In contrast, Q31L-mutant mice showed depressive-like behavior, with deficits in the forced swim test and other measures that could be reversed by treatment with the antidepressant buproprion, but not by rolipram, a PDE4 inhibitor. Brain MRI showed decreased brain volume in L100P-mutant mice (decreased by 13%) and L31-mutant mice (decreased by 6%). Both mutant Disc1 proteins showed decreased binding to PDE4B, and Q31L-mutant mice had decreased PDE4B activity in the brain. Kvajo et al. (2008) generated mice carrying a deletion in the mouse Disc1 gene, resulting in premature truncation, that modeled the disease-associated translocation identified in humans and associated with schizophrenia or bipolar disorder by Blackwood et al. (2001). Mutant mice had alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings showed a deficit in short-term plasticity in the hippocampus of mutant mice. Both homozygous and heterozygous mutant mice showed a selective impairment in working memory during a battery of cognitive tests. The results were consistent with malfunction of neural circuits. Wood et al. (2009) mapped the expression of zebrafish Disc1 and studied its role in early embryonic development using morpholino antisense methods. There was a critical requirement for Disc1 in oligodendrocyte development by promoting specification of Olig2 (606386)-positive cells in the hindbrain and other brain regions. Disruption of neuregulin (Nrg1; 142445) and ErbB (EGFR; 131550) signaling in zebrafish brain development yielded similar defects to those seen in disc1 morphant embryos. Knockdown of Disc1 or Nrg1 caused near total loss of Olig2-positive cerebellar neurons, but caused no apparent loss of spinal motor neurons. Wood et al. (2009) suggested that Disc1 and Nrg1 function in common or related pathways controlling development of oligodendrocytes and neurons from Olig2-expressing precursor cells. In developing mouse hippocampus, Meyer and Morris (2009) showed that in utero electroporation of Disc1 short hairpin RNAs hindered the migration of dentate gyrus granule cells. Disc1 knockdown did not affect the migration of CA1 pyramidal neurons, suggesting that the role of Disc1 in regulating neuronal migration may be spatially restricted within the hippocampus. Meyer and Morris (2009) suggested that DISC1 abnormalities that contribute to the onset of schizophrenia may do so through their influences on hippocampal development. Using in utero RNA interference transfer, Niwa et al. (2010) showed that transient knockdown of Disc1 in prefrontal cortex in mice at embryonic day 14 led to maturation-dependent deficits in mesocortical dopaminergic projections and associated behavioral changes, including those in information processing and cognition. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 SCHIZOPHRENIA, SUSCEPTIBILITY TO | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SCHIZOAFFECTIVE DISORDER, SUSCEPTIBILITY TO | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DISC1, HAPLOTYPE, HEP3 [dbSNP:rs3738401] [dbSNP:rs751229] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hennah et al. (2003) identified a common haplotype, HEP3, that was undertransmitted in Finnish females with schizophrenia (604906). The HEP3 haplotype contains 2 SNPS in the DISC1 gene (rs751229, rs3738401) that span 62 kb from intron 1 to exon 2. Hodgkinson et al. (2004) confirmed underrepresentation of the HEP3 haplotype in individuals with schizoaffective disorder. Hennah et al. (2005) tested whether identified allelic haplotypes of TRAX (602964)/DISC were associated with visual or verbal memory dysfunction known to aggregate with schizophrenia in families. The HEP3 haplotype of DISC1 displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contributed to the observed association in visual working memory. The results provided genetic support for the view that the DISC1 gene contributes to sensitivity to schizophrenia and affects short-term visual memory functions. Among Finnish twin pairs discordant for the HEP3 haplotype, Li et al. (2007) found a significant association between presence of the haplotype and decreased sociability, suggesting that DISC1 has an effect on social behavior. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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