Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia

Mouaffak, Fayçal; Kébir, Oussama; Chayet, M.; Tordjman, Sylvie; Vacheron, Marie-Noëlle; Millet, Bruno; Jaafari, Nématollah; Bellon, Alfredo; Olié, Jean‐Pierre; Krebs, Marie‐Odile

doi:10.1038/tpj.2010.40

Cited by 36 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study implicating the R264Q variant in schizophrenia suggests that treatment-resistant schizophrenia, whereby patients do not respond to typical antipsychotic medication, are likely to carry the minor allele of the R264Q variant (Mouaffak et al, 2010). This is very interesting, as these findings suggest that this SNP may regulate the efficacy of antipsychotic treatment.…”

Section: Discussionmentioning

confidence: 99%

Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development

Singh

Rienzo

Drane

et al. 2011

Neuron

115

111

View full text Add to dashboard Cite

Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure and function; however, it is unknown how this occurs. Here we demonstrate using mouse, zebrafish and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q and L607F, but not S704C, do not activate Wnt signaling compared to wild type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development, and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development

Singh

Rienzo

Drane

et al. 2011

Neuron

115

111

View full text Add to dashboard Cite

show abstract

“…11 While it therefore appears that DISC1 acts on known therapeutic pathways, it is perhaps even more exciting that variation in DISC1 may be associated with forms of schizophrenia resilient to treatment. 12 While these results have yet to be successfully replicated, 13 they imply that DISC1 may provide a target for the development of treatments for some of the sufferers of major mental illness for whom current pharmaceuticals are of limited or no use.…”

mentioning

confidence: 99%

DISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness

Soares

Carlyle

Bradshaw

et al. 2011

ACS Chem. Neurosci.

109

129

View full text Add to dashboard Cite

Disrupted in schizophrenia 1 (DISC1) is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare DISC1 variants associated with major mental illness. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes.

show abstract

“…In a very recent meta-analysis, it was concluded that there was no evidence that common variants at the DISC1 locus are associated with schizophrenia (Mathieson et al, 2012). Efforts have also been carried out to find out if SNPs of the DISC1 gene have an association with treatment resistance in schizophrenia, but results have also been inconclusive; one study had positive (Mouaffak et al, 2011), yet another had negative, results (Hotta et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Adverse Life Events and Disrupted in Schizophrenia-1 (DISC1) Gene Polymorphisms on Acute Symptoms of Schizophrenia

Sayin

Yüksel

Konac

et al. 2013

DNA and Cell Biology

View full text Add to dashboard Cite

The aim of this study was to evaluate the effects of traumatic childhood events and recent adverse life events, as well as the Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on types of last acute symptoms of patients with schizophrenia. Hundred patients with schizophrenia were given the Childhood Trauma Questionnaire, the Social Readjustment Rating Scale, Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), and Calgary Depression Scale for Schizophrenia (CDSS). The patients' and healthy controls' DISC1 gene was evaluated for the -274G>C, c.791G>A, and c.2110A>T polymorphisms. There was no statistically significant difference with regard to the DISC1 gene polymorphisms between patient and healthy control groups. No significant relationship was found between the -274G>C, c.791G>A, and c.2110A>T haplotypes and development of different acute symptoms of schizophrenia. Having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=-67.547, -21.473; p=0.00) and BPRS-1 scores (95% CI=-51.405, -6.885; p=0.01), whereas emotional abuse at childhood significantly affected SANS scores (95% CI=-37.300, -10.401; p=0.00). This study shows that features of acute symptoms in schizophrenia are not influenced by the polymorphisms on the DISC1 gene, but are influenced by recent adverse life events and emotional abuse at childhood.

show abstract

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia

Cited by 36 publications

References 50 publications

Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development

Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development

DISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness

Effects of the Adverse Life Events and Disrupted in Schizophrenia-1 (DISC1) Gene Polymorphisms on Acute Symptoms of Schizophrenia

Contact Info

Product

Resources

About