Several genetic studies point to involvement of DISC1 in major psychiatric illness, including schizophrenia and bipolar disorder, but to date the only causal variant that has been definitively identified is the translocation between human chromosomes 1 and 11 that co-segregates with major mental illness in a large Scottish family and which directly disrupts the DISC1 gene (Millar at al., 2000). It has been speculated that a truncated form of DISC1 may be expressed from the translocated allele and, if so, that this could exert a dominant-negative effect, but there is no such evidence from studies of the translocation cases. Rather, the evidence from studies of lymphoblastoid cell lines carrying the translocation suggests that haploinsufficiency is the most likely disease mechanism in this family (Millar et al., 2005). The unresolvable caveat to this, of course, is that it has not been possible to determine whether this is true also for the brain. Moreover, it is far from certain that any productive product from the translocation chromosome would be a perfectly truncated protein encoded by all the remaining exons, as opposed to an exon-skip isoform, with or without a hybrid protein component borrowing sequence information from chromosome 11. What does seem likely from other human studies is that additional genetic mechanisms, including missense mutations, altered expression, and possibly also copy number variation, play a role in the generality of DISC1 as a risk factor.

The evidence in support of DISC1 as an important biological determinant across a spectrum of major mental illness has now received a further boost from the study in PNAS by Hikida et al. The Sawa lab describes a transgenic approach where a truncated human DISC1 protein is expressed from a CAMKII promoter. The truncation was designed to mimic the hypothetical truncation arising from the Scottish translocation. This forebrain-specific promoter confers preferential expression of the transgene at neonatal stages, as distinct from the expression of the endogenous protein, which is abundant from embryonic development into adulthood. This model therefore permits investigation of the effect of the truncated protein in the forebrain within a specific developmental window, against a background of endogenous mouse DISC1 expression. Since there is no evidence for production of a truncated protein from the translocated allele, the relevance of this model to psychiatric illness remains unclear. However, on the positive side and from a functional perspective, dominant-negative effects as a consequence of expressing the truncated protein have already been demonstrated in cultured cells, altering the subcellular distribution of DISC1 and interaction with DISC1 partner proteins. Moreover, expression of the truncated form of DISC1 mimics downregulation of DISC1 in vivo, inhibiting migration of neurons in the developing mouse cortex (Kamiya et al., 2005). Thus, this model has the genuine potential to enhance our understanding of the biology of DISC1.

This is, in fact, the third study describing mice expressing modified DISC1 alleles. In the first study, Gogos and colleagues (Kioke et al., 2006) studied the effects of a modified DISC1 allele carrying a spontaneous 25 bp deletion in exon 6 that is present in all 129 mouse strains (Koike et al., 2007; see SRF related news story). This allele additionally has an artificial stop codon in exon 8 and a downstream polyadenylation signal. After back-crossing this mutagenised version of the 129 allele onto a C57Bl6 background, they reported a deficit in an assay of working memory in both heterozygous and homozygous mutants, but other standard behavioral tests were unaltered or unreported, and there were no anatomical, electrophysiological, or pharmacological studies included. In the second study, one led by the Roder laboratory, Toronto, we described two mouse strains with missense mutations in exon 2, Q31L and L100P (Clapcote et al., 2007). Reductions in brain volume, deficits in a range of standard behavioral tests, and responses to pharmacological treatments were reported, which can be summarized as consistent with the 100P mutants displaying schizophrenia-like phenotypes and the 31L mutants, mood disorder-like phenotypes. There is a frustrating dearth of consistent biomarkers for schizophrenia, but one of the best replicated findings is by brain imaging of enlarged ventricles in schizophrenia (also, but less markedly, in bipolar disorder). Adding to the observations of Clapcote et al., arguably the most striking claim by Hikida et al. is for altered ventricular brain volume and reduced brain laterality following neonatal transgenic overexpression of truncated DISC1. Additionally, behavioral tests were reported that overlap in part with those reported earlier by Clapcote et al. That three studies all describe behavioral abnormalities consistent with modeling components of schizophrenia is reassuring. That there are clear differences, too, between the phenotypes should come as no surprise either, given the important differences in terms of genetic lesion and developmental expression. Other mouse models are in the pipeline and they, too, will be welcomed. Indeed, this is very much what is needed for the field to move forward. But we should do so with some caution, paying careful attention to the specific nature of the models, what they can and cannot tell us about DISC1 biology, and what they may or may not tell us about the human condition. Although none of these models relates directly to a known causal variant, it appears that the mouse models concur with the human genetic studies in suggesting that there are likely to be several routes by which DISC1 can perturb brain function leading to characteristics of human mental illness. What we need now is for the human genetic studies to catch up with the mouse so that defined pathognomic variants can be modeled.

View all comments by David J. Porteous
View all comments by Kirsty Millar

A new mouse model from the Sawa lab strengthens the evidence for the candidate gene DISC1 playing a role in psychosis and mood disorders. This important paper is the first to address one potential disease mechanism, that of a dominant-negative effect. Expression of the C-terminal deletion of human DISC1—which represented the original rearrangement found by the Porteous group in the Scottish families with schizophrenia and depression—in transgenic mice driven by the α CaMKII promoter, first described by Mark Mayford when a postdoctoral fellow in the Kandel lab, leads to mice showing behaviors consistent with schizophrenia and depression, with enlarged lateral ventricles. Since the Sawa group expressed the human C-terminal truncation in mouse with no change in mouse DISC1 levels, they feel this supports a dominant-negative mechanism. More direct experiments are required. For example, create a null mutant mouse for DISC1 and express the full-length and truncated human DISC1 under the influence of their own promoter in transgenic mice using human BACs. Full-length human DISC1 would, hopefully, rescue the null. If so, then a mixture of full-length and truncated DISC1 proteins could be tried. No rescue by the mixture of full-length and truncated proteins would suggest a dominant-negative mechanism.

The Porteous group has shown no detectable DISC1 protein in lymphoblasts from the patients, and put forward the following implicit model. The C-terminal truncation of DISC1 makes the protein unstable and sensitive to degradation, a plausible alternative notion. In my opinion both are likely in different schizophrenia patients with perturbations in DISC1, most of which are alterations other than the C-terminal truncation. Some have SNPs that lead to as yet uncharacterized disease. It has been shown by the Sawa lab that mice with a partial RNAi knockdown of DISC1 show perturbations in brain development, and if aged to 8-12 weeks these mice might have shown behavioral and neuropathological hallmarks of schizophrenia and depression. There is currently no null mutation in the mouse that would address this issue, although DISC1 is one of the genes being targeted in the NIH knockout mouse project. Fortunately, there are now several mouse models—the more the better. The Gogos lab has a 25bp deletion in exon 6 that removes some, but not all isoforms. The Roder lab used a reverse genetic screen of an ENU archive to generate two missense mutants in non-conserved amino acids. The phenotypes of all these lines are nicely summarized in the Sawa paper. This work represents a step forward in our understanding of the DISC1 gene.

View all comments by John Roder