[5] In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion.
Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, clinical depression, bipolar disorder, and other psychiatric conditions.
According to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (or DSM-IV) criteria, sixteen of the 34 individuals identified as having the genetic mutation were diagnosed with psychiatric problems.
In zebrafish, DISC1 is essential for forebrain development and GSK3/β-catenin signaling, while in mice the DISC1-GSK3 pathway regulates proliferation of neural progenitor cells in the cortex and adult dentate gyrus.
[20] DISC1 is highly expressed during critical periods of brain development, particularly in the embryonic ventricular and subventricular zones of the cortex, where neural progenitor cells are found.
[25] DISC1-FEZ1 interaction is enhanced during neuro-differentiation, and expression of the FEZ1-binding domain of DISC1 has a dominant negative effect on neurite outgrowth, which implies co-operation of DISC1 and FEZ1 in this process.
[18][21] DISC1 shows strong interaction with the microtubule-associated protein MAP1A that controls the polymerization and stabilization of microtubule networks in neurons, and thereby influence cell shape and intracellular transport of vesicles and organelles.
[24] DISC1 is localized to the centrosome, the primary microtubule organizing center of the cell, via interaction with nuclear distribution gene homologue-like 1 (NDEL1, also called NUDEL), where it is part of a protein complex involved in cytoskeletal processes of neuronal migration, including nucleokinesis and neurite outgrowth.
[27][28] Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine an isoleucine mis-sense mutation in exon 24 which may change the structure and function of PCM1 (rs370429).
A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site.
[24] Aberrations of DISC1 are considered a generalized risk factor in major psychiatric diseases and have also been implicated in memory deficits and abnormal patterns of brain activity.
[17][30] DISC1 translocation increases the risk of developing schizophrenia, bipolar disorder, or major depression by about 50-fold in comparison to the general population.
[18] However, no specific variant is consistently associated with development of mental disorders, indicating allelic heterogeneity in psychiatric disease.
[20] DISC1 has been associated with neurological abnormalities such as delusions, deficits in long term and working memory, diminution of gray matter volume in hippocampal and prefrontal regions.
[20] Mice expressing the dominant-negative form of DISC1 have been shown to be increasingly susceptible to impaired reality testing, a hallmark of psychosis.
A recent family study has reported a large chromosome 1 deletion that includes loss of DISC1 in a young boy diagnosed with autism.
[30] Transgenic model organism strains generated with mutated or absent DISC1 suggest that the gene may contribute to at least some autistic abnormalities.
[30] Mice with lowered levels of DISC1 expression exhibit abnormal response to electrical stimulation, a decrease of dopamine synthesis, and an inability to filter unnecessary sensory information.
Additional family members with the original translocation who developed major psychotic illness, including bipolar disorder, were identified.
[33] As DISC1 investigation continues to be an emerging area of study, many unanswered questions regarding the biological function of the protein and its implications in psychiatric disorders remain.
In depth understanding of DISC1 as a genetic risk factor for psychiatric disorders provides a possible target for developing new drug therapies and preventative measures.
[18] Definitive genetic architecture, risk distribution, and their correlation with prognosis is crucial to determining response to new drug treatments.
[18] Furthermore, posttranslational processing and its effect on isoform expression, which also contributes to protein function and may be involved in some forms of disease, remains to be studied.
[18][31] The ability to predict the impact of different types of mutations on protein function and resulting psychiatric phenotype is crucial for the development of targeted treatments.
[31] Family studies continue to provide an important approach towards deepening understanding of the biological nature of the gene and its clinical implications.