The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density.
The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density.
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精神分裂症相关错义变异 rs13107325 调节树突棘密度
DOI：
10.1038/s41398-022-02137-z
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发表时间：
2022-09-02
影响因子：
6.8
通讯作者：
Luo, Xiong-Jian
中科院分区：
文献类型：
--
作者：
Li, Shiwu;Ma, Changguo;Li, Yifan;Chen, Rui;Liu, Yixing;Wan, Li Pear;Xiong, Qiuxia;Wang, Chuang;Huo, Yongxia;Dang, Xinglun;Yang, Yongfeng;Lv, Luxian;Chen, Xi;Sheng, Nengyin;Li, Wenqiang;Luo, Xiong-Jian
最近的全基因组关联研究（GWASs）显示，SLC 39 A8中的错义变异rs 13107325（C/T，p.Ala391Thr）与精神分裂症的关联性很强，提示这种非同义风险变异具有潜在的致病性。然而，这种错义变异如何赋予精神分裂症风险仍然未知。我们构建了一个敲入小鼠模型（通过在小鼠SLC 39 A8的第393位氨基酸（SLC 39 A8-p.393T）处引入一个苏氨酸，其对应于人SLC 39 A8的rs 13107325（p.Ala391Thr）），以探讨该错义变体在精神分裂症发病机制中的潜在作用和生物学效应。我们评估了基因敲入小鼠的多种表型和性状（与rs 13107325相关），包括体重和脑重、SLC 39 A8转运的金属离子（包括镉、锌、锰和铁）浓度、血脂、神经干细胞（NSCs）的增殖和迁移、皮质发育、行为和认知、转录组、树突棘密度和突触传递。许多测试的表型在SLC 39 A8-p.393T敲入和野生型小鼠中没有显示出差异。然而，我们发现与野生型相比，SLC 39 A8-p.393T敲入小鼠的脑和血液中的锌浓度失调，验证了rs 13107325的功能。进一步分析表明，与野生型相比，SLC 39 A8-p.393T敲入小鼠的皮质树突棘密度显著降低，表明SLC 39 A8-p.393T在树突棘形态发生中的重要作用。这些结果表明，SLC 39 A8-p.393T敲入导致树突棘密度降低，因此模拟了在精神分裂症中观察到的树突棘病理学。我们的研究表明，rs 13107325可能通过调节锌浓度和树突棘密度赋予精神分裂症风险，这是精神分裂症中经常报告减少的特征。
The missense variant rs13107325 (C/T, p.Ala391Thr) inSLC39A8consistently showed robust association with schizophrenia in recent genome-wide association studies (GWASs), suggesting the potential pathogenicity of this non-synonymous risk variant. Nevertheless, how this missense variant confers schizophrenia risk remains unknown. Here we constructed a knock-in mouse model (by introducing a threonine at the 393th amino acid of mouse SLC39A8 (SLC39A8-p.393T), which corresponds to rs13107325 (p.Ala391Thr) of human SLC39A8) to explore the potential roles and biological effects of this missense variant in schizophrenia pathogenesis. We assessed multiple phenotypes and traits (associated with rs13107325) of the knock-in mice, including body and brain weight, concentrations of metal ions (including cadmium, zinc, manganese, and iron) transported by SLC39A8, blood lipids, proliferation and migration of neural stem cells (NSCs), cortical development, behaviors and cognition, transcriptome, dendritic spine density, and synaptic transmission. Many of the tested phenotypes did not show differences in SLC39A8-p.393T knock-in and wild-type mice. However, we found that zinc concentration in brain and blood of SLC39A8-p.393T knock-in mice was dysregulated compared with wild-types, validating the functionality of rs13107325. Further analysis indicated that cortical dendritic spine density of the SLC39A8-p.393T knock-in mice was significantly decreased compared with wild-types, indicating the important role of SLC39A8-p.393T in dendritic spine morphogenesis. These results indicated that SLC39A8-p.393T knock-in resulted in decreased dendritic spine density, thus mimicking the dendritic spine pathology observed in schizophrenia. Our study indicates that rs13107325 might confer schizophrenia risk by regulating zinc concentration and dendritic spine density, a featured characteristic that was frequently reported to be decreased in schizophrenia.
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影响因子：
3.7
作者：
Hermann ER;Chambers E;Davis DN;Montgomery MR;Lin D;Chowanadisai W
通讯作者：
Chowanadisai W
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
16.6
作者：
Haller G;McCall K;Jenkitkasemwong S;Sadler B;Antunes L;Nikolov M;Whittle J;Upshaw Z;Shin J;Baschal E;Cruchaga C;Harms M;Raggio C;Morcuende JA;Giampietro P;Miller NH;Wise C;Gray RS;Solnica-Krezel L;Knutson M;Dobbs MB;Gurnett CA
通讯作者：
Gurnett CA
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay