An alternative splicing hypothesis for neuropathology of schizophrenia: evidence from studies on historical candidate genes and multi-omics data
An alternative splicing hypothesis for neuropathology of schizophrenia: evidence from studies on historical candidate genes and multi-omics data
复制标题
精神分裂症神经病理学的另一种剪接假说：历史候选基因和多组学数据研究的证据
DOI：
10.1038/s41380-021-01037-w
复制
发表时间：
2021-03
影响因子：
11
通讯作者：
Ming Li
中科院分区：
文献类型：
--
作者：
Chu-Yi Zhang;Xiao Xiao;Zhuohua Zhang4;Zhonghua Hu;Ming Li
精神分裂症风险基因如DRD 2、GRM 3和DISC 1的选择性剪接已被广泛描述。然而，通过遗传分析确定的越来越多的精神分裂症风险基因的选择性剪接特征仍然相对不透明。最近，基于短读段RNA测序的人脑中的转录组学分析已经发现了许多“局部剪接”事件（例如，外显子跳跃连接）与精神分裂症的遗传风险相关，进一步的分子表征已经鉴定出新的剪接异构体，如AS 3 MTd 2d 3和ZNF 804 AE 3E 4。此外，精神分裂症风险基因（例如，CACNA 1和NRXN 1）揭示了多种以前未注释的具有治疗潜力的脑丰富的异构体，并且KCNH 2 -3.1和Ube 3a 1的功能分析为在体外和体内研究此类剪接异构体提供了实例。这些发现表明，选择性剪接可能是精神分裂症遗传风险的重要分子机制，然而，人脑转录组的不完整注释可能限制了我们对精神分裂症发病机制的理解，迫切需要进一步努力阐明这些转录特征，以深入了解这种疾病-相关的脑生理学和病理学以及将遗传发现转化为新的治疗靶点。
Alternative splicing of schizophrenia risk genes, such asDRD2,GRM3, andDISC1, has been extensively described. Nevertheless, the alternative splicing characteristics of the growing number of schizophrenia risk genes identified through genetic analyses remain relatively opaque. Recently, transcriptomic analyses in human brains based on short-read RNA-sequencing have discovered many “local splicing” events (e.g., exon skipping junctions) associated with genetic risk of schizophrenia, and further molecular characterizations have identified novel spliced isoforms, such asAS3MTd2d3andZNF804AE3E4. In addition, long-read sequencing analyses of schizophrenia risk genes (e.g.,CACNA1CandNRXN1) have revealed multiple previously unannotated brain-abundant isoforms with therapeutic potentials, and functional analyses ofKCNH2-3.1 andUbe3a1have provided examples for investigating such spliced isoforms in vitro and in vivo. These findings suggest that alternative splicing may be an essential molecular mechanism underlying genetic risk of schizophrenia, however, the incomplete annotations of human brain transcriptomes might have limited our understanding of schizophrenia pathogenesis, and further efforts to elucidate these transcriptional characteristics are urgently needed to gain insights into the illness-correlated brain physiology and pathology as well as to translate genetic discoveries into novel therapeutic targets.
登录
查看更多内容
DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
3.4
作者：
Profaci, Caterina P.;Krolikowski, Kristyn A.;Olszewski, Rafal T.;Neale, Joseph H.
通讯作者：
Neale, Joseph H.
DOI：
--
发表时间：
1987
期刊：
The Hillside journal of clinical psychiatry
影响因子：
--
作者：
D. Javitt
通讯作者：
D. Javitt
影响因子：
11
作者：
Tao R;Davis KN;Li C;Shin JH;Gao Y;Jaffe AE;Gondré-Lewis MC;Weinberger DR;Kleinman JE;Hyde TM
通讯作者：
Hyde TM
豹纹珊瑚石斑鱼（Plectropomus leopardus）全基因组测序及肤色调控机制及适应性进化探索
影响因子：
4.9
作者：
Yang Yang;Lina Wu;Jingfang Chen;Xi Wu;Junhong Xia;Zining Meng;Xiaochun Liu;Haoran Lin
通讯作者：
Haoran Lin