Insoluble DISC1–Boymaw fusion proteins generated by DISC1 translocation

Zhou, Xianjin; Chen, Qi; Schaukowitch, Katie; Kelsoe, John R.; Geyer, Mark A.

doi:10.1038/mp.2009.127

Cited by 28 publications

(42 citation statements)

References 14 publications

(2 reference statements)

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“…There is some suggestion that this gene may have an inhibitory interaction with the brain expressed CHORDC1 gene, which has been implicated in stress response. Zhou et al (2010) found that the DISC1- DISC1FP1 fusion protein is insoluble, in contrast to the DISC1FP1 -DISC1 fusion protein. Insoluble DISC1 proteins have been found to aggregate in the brains of patients with schizophrenia and it is suggested that this limits the ability of DISC1 to interact with necessary binding partners (Leliveld et al 2008).…”

Section: Discussionmentioning

confidence: 94%

“…Concerning a possible role for DISC1FP1 in schizophrenia, Zhou and colleagues (2010) identify that within the human brain there is novel expression of a single exon of DISC1FP1 that is not present in lymphoblastoid cells, additionally there are several splice variations of the gene present in human thalamus. There is some suggestion that this gene may have an inhibitory interaction with the brain expressed CHORDC1 gene, which has been implicated in stress response.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the DISC1 translocation partner (11q14.3) in genetic risk of schizophrenia

Debono¹,

Topless

Markie³

et al. 2012

Genes Brain and Behavior

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The Disrupted-in-Schizophrenia 1 (DISC) locus on human chromosome 1 was identified as a consequence of its involvement in a balanced translocation (1;11)(q42.1;q14.3) segregating with major psychiatric disorders in a Scottish family. Recently a comprehensive meta-analysis of genome-wide association scan data found no evidence that common variants of DISC1 (1q42.1) are associated with schizophrenia. Our aim was to test for association of variants in the 11q14.3 translocation region with schizophrenia. The 11q14.3 region was examined by meta-analysis of genome-wide scan data made available by the Genetic Association Information Network (GAIN) and other investigators (non-GAIN) through dbGap. P values were adjusted for multiple testing using the false discovery rate (FDR) approach. There were no SNPs significant (P<0.05) after correction for multiple testing in the combined schizophrenia data set. However one SNP (rs2509382) was significantly associated in the males only analysis with PFDR = 0.024. Whilst the relevance of the (1;11)(q42.1;q14.3) translocation to psychiatric disorders is currently specific to the Scottish family, genetic material in the chromosome 11 region may contain risk variants for psychiatric disorders in the wider population. The association found in this region does warrant follow-up analysis in further sample sets.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Analysis of the DISC1 translocation partner (11q14.3) in genetic risk of schizophrenia

Debono¹,

Topless

Markie³

et al. 2012

Genes Brain and Behavior

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“…Human DISC1 breakpoint mutation has been reported to generate fusion proteins by spanning over chromosome 1 and 11, generating aggregation-prone protein species (Zhou et al, 2010; Ji et al, 2014; Ji et al, 2015). Similarly, recent studies demonstrated that DISC1 protein is prone to self-aggregation or co-aggregation with other proteins such as dysbindin (Leliveld et al, 2008; Ottis et al, 2011; Atkin et al, 2012), likely due to impairment of the protein quality control or cellular clearance systems.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Utility and validity of DISC1 mouse models in biological psychiatry

et al. 2016

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We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10–15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

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“…However, translocations may also result in formation of one or several fusion transcripts potentially producing a gain-of-function effect. This phenomenon is mostly known in cancer; however, a few cases where constitutional chromosomal translocations result in fusion transcripts have been reported in patients with both schizophrenia (Zhou et al, 2010;Eykelenboom et al, 2012), intellectual disability (Nothwang et al, 2001) and cerebellar malformations (Di Gregorio et al, 2013). Fusion transcripts may thus also play a yet unknown role in other neurological disorders (Holt et al, 2012).…”

Section: Introductionmentioning

confidence: 97%