Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies. Mus musculus

Recent genetic studies by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium have identified that protein-truncating variants of exportin 7 (XPO7) can increase the risk of schizophrenia (odds ratio, 28.1). In this study, we demonstrated that mice with Xpo7 haploinsufficiency (Xpo7+/- mice) present with cognitive and social behavioral impairments. Through proteome analysis using immunoprecipitation and frontal cortex nuclear isolation of Xpo7+/- mice, we identified 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. In addition, through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7+/- mice differentiating between the onset and progressive stages, we identified 284 gene expression changes that correlated with these stages. These genes encompass the high-odds risk genes of schizophrenia identified by the SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach identified 15 gene expression changes in the frontal cortex that correlated with the progressive stages. In conclusion, our findings indicate the importance of investigating whether the interactions among the high-risk genes identified by SCHEMA contribute to a common schizophrenia pathology and underscore the significance of stage-dependent analysis.