A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.
A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.
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精确敲入小鼠模型证实了导致常染色体显性外侧颞叶癫痫的新型 LGI1 突变
DOI：
10.1111/cns.13761
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发表时间：
2022-03
影响因子：
5.5
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Hu P;Wu D;Zang YY;Wang Y;Zhou YP;Qiao F;Teng XY;Chen J;Li QQ;Sun JH;Liu T;Feng HY;Zhou QG;Shi YS;Xu Z
本研究旨在使用精确敲入小鼠模型，探索在常染色体显性遗传侧颞叶癫痫（ADLTE）家族中鉴定的富含亮氨酸胶质瘤失活1基因（LGI 1）突变的病理机制。通过全外显子测序发现一个ADLTE家系中存在一种新的LGI 1突变c.152A>G; p.Asp51Gly。通过产生精确表型模仿人类患者癫痫症状的Lgi 1D 51 G敲入小鼠来探索突变的病理机制。Lgi 1D 51 G/D51 G小鼠表现出自发性反复全身性癫痫发作和过早死亡。Lgi 1D 51 G/+小鼠有部分癫痫，其中一半在脑电图上显示癫痫样放电。他们还表现出对惊厥剂戊四唑的敏感性增强。从机制上讲，D51 G基因敲入小鼠大脑中Lgi 1的分泌受损，蛋白质水平急剧下降。抗癫痫药物卡马西平、奥卡西平和丙戊酸钠均能延长Lgi 1D 51 G/D51 G小鼠的存活时间，其中奥卡西平的作用最明显。我们在人类中发现了一种新的导致癫痫的LGI 1突变。Lgi 1D 51 G/+小鼠模型精确地模拟了人类患者的癫痫症状，可能成为未来研究癫痫发病机制和潜在疗法的有用工具。 Lgi 1 D51 G基因敲入小鼠（c.152A>G; p. Asp 51 Gly）非常精确地表型模拟了一个新的中国ADLTE家族中人类患者的癫痫症状，将成为未来研究癫痫发病机制和潜在治疗的有用工具。
This study aimed to explore the pathomechanism of a mutation on the leucine‐rich glioma inactivated 1 gene (LGI1) identified in a family having autosomal dominant lateral temporal lobe epilepsy (ADLTE), using a precise knock‐in mouse model. A novel LGI1 mutation, c.152A>G; p. Asp51Gly, was identified by whole exome sequencing in a Chinese family with ADLTE. The pathomechanism of the mutation was explored by generating Lgi1D51G knock‐in mice that precisely phenocopied the epileptic symptoms of human patients. The Lgi1D51G / D51G mice showed spontaneous recurrent generalized seizures and premature death. The Lgi1D51G /+ mice had partial epilepsy, with half of them displaying epileptiform discharges on electroencephalography. They also showed enhanced sensitivity to the convulsant agent pentylenetetrazole. Mechanistically, the secretion of Lgi1 was impaired in the brain of the D51G knock‐in mice and the protein level was drastically reduced. Moreover, the antiepileptic drugs, carbamazepine, oxcarbazepine, and sodium valproate, could prolong the survival time of Lgi1D51G / D51G mice, and oxcarbazepine appeared to be the most effective. We identified a novel epilepsy‐causing mutation of LGI1 in humans. The Lgi1D51G /+ mouse model, precisely phenocopying epileptic symptoms of human patients, could be a useful tool in future studies on the pathogenesis and potential therapies for epilepsy. Lgi1 D51G knock‐in mice (c.152A>G; p. Asp51Gly) quite precisely phenocopied the epileptic symptoms of the human patients in a novel Chinese ADLTE family and would be a useful tool for future study on the pathogenesis and potential therapy for epilepsy.
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