DISC1 at 10: connecting psychiatric genetics and neuroscience

Abstract

Psychiatric genetics research, as exemplified by the DISC1 gene, aspires to inform on mental health etiology and to suggest improved strategies for intervention. DISC1 was discovered in 2000 through the molecular cloning of a chromosomal translocation that segregated with a spectrum of major mental illnesses in a single large Scottish family. Through in vitro experiments and mouse models, DISC1 has been firmly established as a genetic risk factor for a spectrum of psychiatric illness. As a consequence of its protein scaffold function, the DISC1 protein impacts on many aspects of brain function, including neurosignaling and neurodevelopment. DISC1 is a pathfinder for understanding psychopathology, brain development, signaling and circuitry. Although much remains to be learnt and understood, potential targets for drug development are starting to emerge, and in this review, we will discuss the 10 years of research that has helped us understand key roles of DISC1 in psychiatric disease.

Figure 1. The Scottish family, DISC1 gene disruption and native protein

Panel A shows an illustrative sub-portion of the Scottish family tree whose members carry the t(1;11) translocation. Those individuals represented with white shapes have neither the t(1;11) translocation nor a major psychiatric diagnosis. Those individuals represented by light blue shapes carry the t(1;11), but at the time of clinical assessment no major psychiatric diagnosis. Those with a dark blue fill also carry the t(1;11) and have a psychiatric diagnosis of schizophrenia, bipolar disorder or recurrent major depression. Panel B is a visualisation of the balanced translocation between chromosomes 1 (blue) and 11 (orange). This translocation results in a disruption of DISC1 between exons 9 and 10 (c). (c) Is a schematic of the DISC1 genome structure (exons shown as vertical lines) (top) and the native protein structure (below), with the disordered N-terminal [N] head domain (left) and the C-terminal [C] coiled coil domain (right). The translocation site is indicated by a broken arrow.

Figure 2. DISC1: from psychopathology to structure and function

The schema is a conceptual hierarchy linking DISC1 and its binding partners (yellow box) to their cellular localization (purple box), the functions affected by their loss or mutation (blue box), and the psychiatric disorders shown to be linked to DISC1 function (red box).