A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.

Abstract

AIMS:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Ping Hu, Dan Wu, Yan-Yu Zang, Yan Wang, Ya-Ping Zhou, Fengchang Qiao, Xiao-Yu Teng, Jiang Chen, Qing-Qing Li, Jia-Hui Sun, TingTing Liu, Hao-Yang Feng, Qi-Gang Zhou, Yun Stone Shi, Zhengfeng Xu
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 28 Issue 2 Pg. 237-246 (02 2022) ISSN: 1755-5949 [Electronic] England
• PMID: 34767694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Chemical References

• Intracellular Signaling Peptides and Proteins
• LGI1 protein, human

Topics

• Animals
• Child
• Disease Models, Animal
• Epilepsy, Temporal Lobe (genetics, physiopathology)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pedigree