RT Journal Article
SR Electronic
T1 Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 005710
DO 10.1101/005710
A1 Baohu Ji
A1 Kerin K. Higa
A1 Minjung Kim
A1 Lynn Zhou
A1 Jared W. Young
A1 Mark A. Geyer
A1 Xianjin Zhou
YR 2014
UL http://biorxiv.org/content/early/2014/05/31/005710.abstract
AB The t(1; 11) translocation appears to be the causal genetic lesion with 70% penetrance for schizophrenia, major depression, and other psychiatric disorders in a Scottish family. Molecular studies identified the disruption of the DISC1 (disrupted-in-schizophrenia 1) gene by chromosome translocation at chromosome 1q42. Our previous studies, however, revealed that the translocation also disrupted another gene, Boymaw (also termed DISC1FP1), on chromosome 11. After translocation, two fusion genes (the DISC1-Boymaw (DB7) and the Boymaw-DISC1 (BD13)) are generated between the DISC1 and Boymaw genes. In the present study, we report that expression of the DB7 fusion gene inhibits both intracellular NADH oxidoreductase activities and protein translation. We generated humanized DISC1-Boymaw mice with gene targeting to examine the in vivo functions of the fusion genes. Consistent with the in vitro studies on the DB7 fusion gene, protein translation activity is decreased in the hippocampus and in cultured primary neurons from the brains of the humanized mice. Expression of Gad67, Nmdar1, and Psd95 proteins are also reduced. The humanized mice display prolonged and increased responses to the NMDA receptor antagonist, ketamine, on various mouse genetic backgrounds. Abnormal information processing of acoustic startle and depressive-like behaviors are also observed. In addition, the humanized mice display abnormal erythropoiesis, which was reported to associate with depression in humans. Expression of the DB7 fusion gene may reduce protein translation to impair brain functions and thereby contribute to the pathogenesis of major psychiatric disorders.