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Annotation

Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet . 2012 Jun 15 ; 21(12):2779-92. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Karoly Mirnics, SRF Advisor
Submitted 21 May 2012 Posted 21 May 2012

The authors report that both the rare DISC1 variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting. Under normal conditions, wild-type DISC1 inhibits the transcriptional activity of ATF4, but this dampening effect is weakened in DISC1 variants 37W and 607F. Furthermore, expression of these schizophrenia-associated disease variants increases endoplasmic reticulum stress levels. It is important to point out that this study found that a putatively causal DISC1 variant (37W) and the common variant (607F) both perturb the nuclear targeting of wild-type DISC1 in a dominant-negative fashion.

It is also noteworthy that previous postmortem studies have found increased chaperone expression in schizophrenia, and while this finding might not have been a direct result of DISC1 genetic variants, it argues that increased cellular stress could be a convergent, critical molecular mechanism characteristic of schizophrenia. This mechanism can clearly arise from multiple genetic vulnerabilities. However, as the majority of people who carry the common variant...  Read more


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Primary News: New Details About DISC1’s Role in Cellular Compartments Emerge

Comment by:  Verian Bader
Submitted 1 June 2012 Posted 1 June 2012

A couple of recently published papers have provided insights into the cell physiology of DISC1. Although DISC1 is one of the most extensively studied susceptibility genes for psychiatric illness, the promoter of DISC1 has not been characterized so far. In a systematic approach based on luciferase reporter genes, Walker et al. (Walker et al., 2012) describe a repressive and an enhancing promoter region upstream of the transcription start. The DISC1 promoter is negatively regulated by FOXP2; hence, affected FOXP2 mutation carriers might show a higher DISC1 expression. Therefore, it would be interesting to know if these FOXP2 mutation carriers also display a higher level of insoluble DISC1, since increased expression leads to an increase of insoluble DISC1 (Leliveld et al., 2008). As a result, and possibly through aggregation, DISC1 loses its ability to bind to specific interaction partners, thereby disrupting some cellular pathways (Atkin et...  Read more


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