A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating K(v)1.1.
A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating K(v)1.1.
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患者来源的癫痫相关 LGI1 突变通过调节 Kv1.1 增加癫痫易感性
DOI：
10.1186/s13578-023-00983-y
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发表时间：
2023-02-20
影响因子：
7.5
通讯作者：
Wei, Jian-She
中科院分区：
文献类型：
--
作者：
Zhou, Lin;Wang, Kang;Xu, Yuxiang;Dong, Bin-Bin;Wu, Deng-Chang;Wang, Zhao-Xiang;Wang, Xin-Tai;Cai, Xin-Yu;Yang, Jin-Tao;Zheng, Rui;Chen, Wei;Shen, Ying;Wei, Jian-She
常染色体显性遗传侧颞叶癫痫（ADLTE）是一种遗传性综合征，由富含亮氨酸的胶质瘤失活1（LGI 1）基因突变引起。已知功能性LGI 1由兴奋性神经元、GABA能中间神经元和星形胶质细胞分泌，并通过结合ADAM 22和ADAM 23调节AMPA型谷氨酸受体介导的突触传递。然而，在家族性ADLTE患者中报告了> 40个LGI 1突变，其中一半以上是分泌缺陷型。这些分泌缺陷型LGI 1突变如何导致癫痫尚不清楚。我们从中国ADLTE家族中发现了一个新的分泌缺陷型LGI 1突变，LGI 1-W183 R。我们在缺乏天然LGI 1的兴奋性神经元中特异性表达突变LGI 1 W183 R，发现该突变下调Kv1.1活性，导致神经元过度兴奋和不规则尖峰，并增加小鼠癫痫易感性。进一步分析表明，恢复兴奋性神经元的Kv1.1可以挽救尖峰放电能力的缺陷，改善癫痫易感性，延长小鼠的寿命。这些结果描述了分泌缺陷型LGI 1在维持神经元兴奋性中的作用，并揭示了LGI 1突变相关癫痫病理学的新机制。在线版本包含补充材料，可通过10.1186/s13578-023-00983-y获得。
Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy. The online version contains supplementary material available at 10.1186/s13578-023-00983-y.
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影响因子：
30.8
作者：
Kalachikov, S;Evgrafov, O;Gilliam, TC
通讯作者：
Gilliam, TC
DOI：
10.1111/ejn.12126
发表时间：
2013-04
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Kim JY;Ash RT;Ceballos-Diaz C;Levites Y;Golde TE;Smirnakis SM;Jankowsky JL
通讯作者：
Jankowsky JL
影响因子：
3.4
作者：
Fourcaud-Trocme, Nicolas;Zbili, Mickael;Kuczewski, Nicola
通讯作者：
Kuczewski, Nicola
影响因子：
11.2
作者：
Gu, WL;Brodtkorb, E;Steinlein, OK
通讯作者：
Steinlein, OK
影响因子：
2.1
作者：
Alvarez, O;Gonzalez, C;Latorre, R
通讯作者：
Latorre, R