Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia

Blackwood, Douglas; Muir, Walter

doi:10.1007/bf03033294

Cited by 61 publications

(40 citation statements)

References 36 publications

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“…Our findings parallel the phenotypical heterogeneity of familial DISC1 cases in the original Scottish pedigree (St Clair et al, 1990;Blackwood et al, 2001;Blackwood and Muir, 2004). We find it remarkable that a single mutation can result in such diverse phenotypes as schizophrenia, bipolar disorder, and recurrent depression.…”

Section: Discussionsupporting

confidence: 79%

“…Patients from the Scottish pedigree are heterozygous for the DISC1 mutation, and given the high penetrance of the phenotype (Blackwood et al, 2001;Blackwood and Muir, 2004), it seems that a loss of 50% of the gene dose is pathogenic (by haploinsufficiency). However, no data have been reported on DISC expression levels in these patients, and compensatory mechanisms may increase gene expression of the healthy allele.…”

Section: Discussionmentioning

confidence: 99%

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Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

Leliveld¹,

Bader²,

Hendriks³

et al. 2008

J. Neurosci.

119

169

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Disrupted-in-schizophrenia 1 (DISC1) and other genes have been identified recently as potential molecular players in chronic psychiatric diseases such as affective disorders and schizophrenia. A molecular mechanism of how these genes may be linked to the majority of sporadic cases of these diseases remains unclear. The chronic nature and irreversibility of clinical symptoms in a subgroup of these diseases prompted us to investigate whether proteins corresponding to candidate genes displayed subtle features of protein aggregation. Here, we show that in postmortem brain samples of a distinct group of patients with phenotypes of affective disorders or schizophrenia, but not healthy controls, significant fractions of DISC1 could be identified as cold Sarkosyl-insoluble protein aggregates. A loss-offunction phenotype could be demonstrated for insoluble DISC1 through abolished binding to a key DISC1 ligand, nuclear distribution element 1 (NDEL1): in human neuroblastoma cells, DISC1 formed expression-dependent, detergent-resistant aggregates that failed to interact with endogenous NDEL1. Recombinant (r) NDEL1 expressed in Escherichia coli selectively bound an octamer of an rDISC1 fragment but not dimers or high molecular weight multimers, suggesting an oligomerization optimum for molecular interactions of DISC1 with NDEL1. For DISC1-related sporadic psychiatric disease, we propose a mechanism whereby impaired cellular control over self-association of DISC1 leads to excessive multimerization and subsequent formation of detergent-resistant aggregates, culminating in loss of ligand binding, here exemplified by NDEL1. We conclude that the absence of oligomer-dependent ligand interactions of DISC1 can be associated with sporadic mental disease of mixed phenotypes.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

Leliveld¹,

Bader²,

Hendriks³

et al. 2008

J. Neurosci.

119

169

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“…The involvement of BICD1 with EEG variability is further suggested because BICD1 interacts directly with LIS1 (37), a protein that also interacts directly with DISC1 (38). Variation at DISC1 has been associated with alteration in the P300-evoked potential, another phenotype of neuronal reactivity (39).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association identifies candidate genes that influence the human electroencephalogram

Hodgkinson

Enoch

Srivastava

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (α), beta (β), and theta (θ) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of θ or α power. SGIP1 was estimated to account for 8.8% of variance in θ power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with θ power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by θ EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism.alcoholism | electroencephalogram | endophenotype | genetics | whole-genome association G enetic studies of behavior and psychiatric disorders are hampered by etiologic heterogeneity of these complex phenotypes. Addiction vulnerability arises from both internalizing (emotional) and externalizing (dyscontrol) behavioral dimensions (1), and both of these broad aspects of behavior are strongly influenced by early life trauma and other gene/environment interactions (2). Etiologic heterogeneity dilutes power to detect genetic effects, and is a reason for failures to detect and replicate genome-wide associations (GWAS) in complex disorders. Increasing sample size does not remove underlying heterogeneity and can introduce additional confounds. In neuropsychiatry, these considerations have led to the use of intermediate phenotypes (or endophenotypes) that are heritable, relevant to disease, and have good measurement properties and assay variation more closely related to gene function (3) as surrogates to probe the underlying biology of complex disorders.

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“…Linkage with schizophrenia alone is also significant, producing an LOD score of 3.6. 2 Blackwood et al 2,3 further reported that the psychiatric presentations are typical with no other distinguishing clinical features. They also reported that, in unaffected translocation carriers, the latency and amplitude of the event related potential (ERP) P300, a measure of the speed and efficiency of information processing, is indistinguishable from that of affected individuals.…”

Section: Genetics Of Disc1 Discoverymentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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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 (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia

Cited by 61 publications

References 36 publications

Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease

Genome-wide association identifies candidate genes that influence the human electroencephalogram

The DISC locus in psychiatric illness

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