title: Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders.
abstract: 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 disrupted-in-schizophrenia 1 (DISC1) 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.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Baohu
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Kerin K
authors.initials: KK
authors.lastname: Higa
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.affiliation: La Jolla High School, 750 Nautilus St., San Diego, CA 92037, USA and.
authors.forename: Lynn
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA, Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92037, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA, Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92037, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA, Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92037, USA xzhou@ucsd.edu.
authors.forename: Xianjin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D000076122:Disks Large Homolog 4 Protein; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D018390:Gene Targeting; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001523:Mental Disorders / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014176:Protein Biosynthesis; D011808:Quinone Reductases / Q000378:metabolism; D062085:RNA, Long Noncoding; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism*; D012606:Scotland; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D044465:White People / Q000235:genetics*
chemical_list: D000076122:Disks Large Homolog 4 Protein; D005968:Glutamate Decarboxylase; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011808:Quinone Reductases; D062085:RNA, Long Noncoding; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C552845:DISC1FP1 non-coding RNA, human; C501444:DLG4 protein, human; C041831:NADH dehydrogenase (quinone); C402565:glutamate decarboxylase 1; C022616:thiazolyl blue