| 1 | Am. J. Hum. Genet. 2013 Oct 93: 697-710 |
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| PMID | 24094746 |
| Title | Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. |
| Abstract | Chimeric genes can be caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. We hypothesize that brain-expressed chimeras may contribute to schizophrenia. Individuals with schizophrenia and control individuals were screened genome wide for copy-number variants (CNVs) that disrupted two genes on the same DNA strand. Candidate events were filtered for predicted brain expression and for frequency < 0.001 in an independent series of 20,000 controls. Four of 124 affected individuals and zero of 290 control individuals harbored such events (p = 0.002); a 47 kb duplication disrupted MATK and ZFR2, a 58 kb duplication disrupted PLEKHD1 and SLC39A9, a 121 kb duplication disrupted DNAJA2 and NETO2, and a 150 kb deletion disrupted MAP3K3 and DDX42. Each fusion produced a stable protein when exogenously expressed in cultured cells. We examined whether these chimeras differed from their parent genes in localization, regulation, or function. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 differed from their parent genes. On the basis of the expression profile of the MATK promoter, MATK-ZFR2 is likely to be far more highly expressed in the brain during development than the ZFR2 parent gene. MATK-ZFR2 includes a ZFR2-derived isoform that we demonstrate localizes preferentially to neuronal dendritic branch sites. These results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization. |
| SCZ Keywords | schizophrenia |
| 2 | Basic Clin. Pharmacol. Toxicol. 2016 Mar -1: -1 |
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| PMID | 26928870 |
| Title | Neto2 Influences on Kainate Receptor Pharmacology and Function. |
| Abstract | Neuropilin tolloid-like protein 2 (NETO2) is an auxiliary subunit of kainate receptors (KARs). It specifically regulates KARs, e.g., slows desensitization and deactivation, increases the rate of recovery from desensitization, promotes modal gating and increases agonist sensitivity. Although the mechanism of NETO2 modulation is still unclear, gain-of-function results from the characterization of GluK1-GluA2 chimeras indicate that the GluK1 sequences included in these chimeras (part or all of the TMD and part of the linkers between the TMDs and LBD) play a key role in NETO2 modulation of KAR. In addition, GluK2 M3-S2 linkers and the D1-D1 dimer interface were also recently identified to be important for NETO2 modulation and some studies suggested that NETO2's N-terminal regions, LDLa domain and the C-terminal regions are important for its modulation of KARs. Although more studies are needed to confirm the roles of these domains and to identify all the domains and residues essential for KAR modulation, these results facilitate our understanding of NETO2 modulation at the structural level, which could potentially aid the development of novel therapies for the treatment of diseases that are associated with KARs, e.g., epilepsies, non-syndromic autosomal recessive mental retardation, schizophrenia and bipolar disorder. This article is protected by copyright. All rights reserved. |
| SCZ Keywords | schizophrenia |