Toyoda Saori, Kikuchi Masataka, Abe Yoshifumi, Tashiro Kyosei, Handa Takehisa, Katayama Shingo, Motokawa Yukiko, Tanaka Kenji F, Takahashi Hidehiko, Shiwaku Hiroki
Department of Psychiatry and Behavioral Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Department of Molecular Genetics, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, 951-8585, Japan.
EMBO Rep. 2025 Feb;26(4):948-981. doi: 10.1038/s44319-024-00362-9. Epub 2025 Jan 7.
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). Here we show 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 identify 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. Through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7 mice differentiating between the onset and progressive stages, we also identify 284 gene expression changes that correlate with these stages. These genes encompass high-odds risk genes of schizophrenia identified by SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach reveals 15 gene expression changes in the frontal cortex that correlate with the progressive stages. 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.
精神分裂症外显子组测序荟萃分析（SCHEMA）联盟最近的基因研究发现，输出蛋白7（XPO7）的蛋白质截短变体可增加精神分裂症风险（优势比为28.1）。在此，我们表明Xpo7单倍剂量不足的小鼠（Xpo7小鼠）存在认知和社会行为障碍。通过使用免疫沉淀和Xpo7小鼠额叶皮质细胞核分离进行蛋白质组分析，我们鉴定出45种与Xpo7相互作用的分子，包括CutC、Rbfox3和Gria3。通过对处于发病期和进展期的Xpo7小鼠额叶皮质和纹状体进行单核RNA测序，我们还鉴定出284种与这些阶段相关的基因表达变化。这些基因包括SCHEMA鉴定出的精神分裂症高优势风险基因，如Gria3、Grin2A、Herc1和Trio。此外，我们的方法揭示了额叶皮质中与进展期相关的15种基因表达变化。我们的研究结果表明，研究SCHEMA鉴定出的高风险基因之间的相互作用是否导致常见的精神分裂症病理具有重要意义，并强调了阶段依赖性分析的重要性。
