Disrupted-In-Schizophrenia-1 (DISC1): A promising lead in molecular analyzes of schizophrenia

Although the genetics of schizophrenia (SZ) remains unresolved, recently both linkage/association studies and cytogenetic approaches have clarified several possible genes for SZ. In the neuropathology of SZ, many now agree that there are at least cytoarchitectural abnormalities such as alterations in synaptic, dendritic, and axonal organization, but clear molecular markers unique to SZ are still missing. In this review, we propose an approach relying on Disrupted-In-Schizophrenia-1 (DISC1), a candidate gene for SZ that may shed light on the molecular neuropathology of SZ. DISC1 was originally identified as the sole disrupted gene with an open reading frame, from a 'unique' Scottish family in which familial SZ and other major mental illnesses occur in tight association with a hereditary chromosomal abnormality. Additional genetic and biochemical approaches using autopsied brains from patients with SZ from other populations than the Scottish family suggest that DISC1 may be implicated not only in the Scottish family but also in 'general' cases of SZ. Furthermore, functional dissection of DISC1 protein indicates that DISC1 is a cytoskeletal protein that plays a key role in neurodevelopment, which may be relevant to the pathogenesis of SZ. Here, we provide a summary of the current updates of studies of DISC1 and their future perspective, especially its possible role in the pathophysiology of SZ, in association with other genetic and environmental factors.