Molecular insights into the function of the DISC locus

• Main Author: Chubb, Jennifer E.
• Published: University of Edinburgh 2007
• Subjects: 616.042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.643165

<i>Disrupted-In-Schizophrenia 1 (DISC1) </i>and <i>Disrupted-In-Schizophrenia 2 (DISC2) </i>have been identified as novel candidate genes for psychiatric illness through analysis of a t(1;11)(q42;q14.3) translocation which segregates with schizophrenia and other major psychiatric illness in a large Scottish family. The <i>DISC</i> locus at 1q42 has been independently implicated in psychiatric illness in multiple populations. This PhD thesis investigates the molecular basis of disease pathogenesis in the t(1;11) family as a result of disruption of <i>DISC1 </i>and <i>DISC2</i>, providing evidence for reduced expression of <i>DISC1</i> within translocation carriers. This refutes previous conjecture of the existence of an abnormal truncated DISC1 protein resulting from the translocation. These data support a disease model of DISC1 haploinsufficiency as the direct cause of illness in this family, which is investigated using RNA interference technology. DISC1 knock-down demonstrates that DISC1 may function in multiple diverse cellular pathways with implications for cAMP signal transduction, cell cycle progression and apoptosis. The complex biology of the DISC1 protein is highlighted by the demonstration of isoform specific sub-cellular localisation which may result in isoforms specific protein-protein interactions. Furthermore DISC1 is shown to be dynamically regulated during neuronal differentiation of embryonic stem cells. The <i>DISC2</i> gene has been successfully extended to its likely 5’ end and novel splicing has been uncovered. This data provides a platform on which to take forward the functional characterisation of <i>DISC2</i> including the current hypothesis that it functions as an anti-sense regulator of <i>DISC1.</i>