Enzyme Translocation In Schizophrenia Pathogenesis

The implication of t(1;11) chromosome translocation in Schizophrenia pathogenesis

Schizophrenia is a severe mental illness that affects approximately 1% of the adult population.1 Due to its complexity, there are many contributions to the genesis of the disease including epigenetic, stochastic and environmental factors, yet studies on families and twins have proved that the genetic component plays a crucial role.2 Multiple Schizophrenia-associated loci have been identified, many of them, revealing little about its mechanisms. In contrast, Disrupted in Schizophrenia 1 (DISC1) represents a particular case. The dysregulation of this gene is caused by the t(1;11) chromosome translocation and although very rare, this mutation shows high correlation
with the disease phenotype.1
The t(1:11) translocation was firstly discovered in a large Scottish family with major psychiatric disorders such as Schizophrenia, depression and psychosis, having a LOD score of 7.1.3( the odds are 107.1 to 1 in favour of linkage between the trait and the disease) The correspondence with Schizophrenia alone was relatively high as well, the LOD score being equal to 3.6.3 The study revealed that on chromosome 1 the DISC1 gene as well as another gene presumed to be involved in its regulation- DISC2- are disrupted by the translocation.4 On chromosome 11, the Boymaw gene (DISC1 Fusion Partner 1) is also deregulated as a result of the mutation. The translocation causes the fusion of the two genes and the generation of two fusion variants, the DISC1-Boymaw (DB7) and the Boymaw-DISC1 (BD13). The breakpoint was localised between exon 8 and 9 of the DISC1 on chromosome 1 and between exon 3 and 4 of the Boymaw on chromosome 11 as depicted in Figure 1.5,6 Figure 1- The DISC1-Boymaw (DB7) and Boymaw-DISC1 (BD13) fusion genes6
The consequences of the t(1;11) translocation on the function of DISC1 have been intensively debated.2 The product encoded by this gene is a molecular scaffold protein, expressed at high levels in the brain, responsible for essential processes such as neuronal migration and differentiation, integration of newborn neurons into the brain circuitry and synapse formation.7,8 It is clear that the disruption of this gene would compromise the normal brain development. Some studies have suggested that the major mechanism for the translocation carriers is haploinsufficiency (half normal levels of DISC1), others have revealed some additional important effects.2,5,8
The first hypothesis that emerged was that the translocation resulted in the generation of a C-terminally truncated DISC1 protein along with reduced levels of expression.9 The effects of the translocation were studied by mimicking the DISC1 interruption in stem cell lines using transcription activator-like effector nucleases (TALENs) or clustered regularly interspaced short palindromic repeats (CRISPR) to cut the DISC1 sequence at the t(1;11) breakpoint.10 It has been found that the splicing between DISC1 exon 8 and the next exon belonging to chromosome 11 led to the introduction of a premature stop codon in the mRNA due to 1 bp insertion or deletion.
This would determine the expression of a shorter protein.10 Moreover, the mRNA containing the premature stop codon was targeted by the nonsense mediated decay pathway which functions to decrease the expression of a potentially harmful truncated protein. Although this mechanism is hypothetical, it has been demonstrated that in cells derived from t(1;11) carriers DISC1 expression is reduced at both mRNA as well as translation level which supports the haploinsufficiency
model.3
The expression of DB7 fusion gene was also found to decrease rRNA synthesis and general protein translation in both cell studies and in transgenic DISC1-Boymaw mice.5 In mice this was suggested by a reduction in the cellular levels of Gad67, Nmdar1 and Psd95 proteins, in spite of normal levels of mRNA transcripts for the corresponding genes.5 Optimal translation is necessary for neural plasticity and in fact, hypermethylation of rRNA gene promoter has been associated with suicide, cognitive impairment and Alzheimer's disease.11,5 Given that rRNA synthesis is a factor that determines ribosome biogenesis, low levels of rRNA will decrease protein translation as well.5 In addition, the transgenic mice also showed enlarged ventricles, reduced cerebral cortex and thinning of neuronal layers, symptoms that are very common to Schizophrenic
individuals.12 Furthermore, J.E. Eykeleboom et al. discovered that, in lymphoblastoid cell cultures, the translocation determines the formation of chimeric transcripts.8 Aberrant proteins such as CP1, CP60 and CP69 are encoded by these transcripts and consist of 597 amino acids, which represent the C-terminally truncated DISC1 protein, plus 1, 60 and 69 amino acids, encoded by the Boymaw sequence.8 The α-helical content is increased by the additional amino acids in the structures of CP60 and CP69, causing the formation of large, stable proteins. Clustering of these proteins in the mitochondria, which they specifically target, results in a loss of mitochondrial membrane potential. In this way processes such as proliferation, differentiation and synaptic signalling can be severely affected.8,13
The above-mentioned studies were carried on animals and cell cultures, however it has also been proved that in the Scottish family members (where t(1;11) was firstly discovered) the translocation is associated with deficient white matter connectivity in neural pathways specifically correlated with Schizophrenia such as the corpus callosum and fibres projecting to prefrontal regions.4 Impairment in these structures determines poor information transmission between the two cerebral hemispheres and loss of prefrontal control over regions involved in the regulation of behaviour and cognitive processing.4,14 Consistent with these findings, the DISC1 gene was shown to be heavily expressed in glial cells.15 Thus the translocation may disrupt oligodendrocyte differentiation causing deficient axonal myelination and abnormal white matter connectivity.15 Also supporting the hypothesis of t(1;11) translocation generating Schizophrenia symptomatology, a study by Doyle et al. finds striking similarities between the patterns of cortical thickness of the mutation carriers (belonging to the Scottish family) and non-carriers schizophrenic patients.1 Surprisingly, this has been observed despite the fact that the carriers had heterogeneous phenotypes ( bipolar disorder, major depression, Schizophrenia) which suggests that DISC1 has rather pleiotropic effects.1
The precise mechanism of the translocation and the functions of DISC1 gene are not clearly known, although it has been intensely researched. This has been due to the small number of individuals carrying the translocation and to the fact that it is difficult to reproduce a psychiatric illness and to interpret the effects of the translocation in non-humans. Moreover, many genes are involved in the development of Schizophrenia. Nevertheless, taking into account the molecular mechanism-phenotype correlation of the t(1;11), its implication in the pathology of Schizophrenia in the Scottish family still remains uncontested. As a result, further research needs to be conducted as this mutation is biologically informative and can potentially help in disentangling the mechanistic basis of psychiatric illness.