A novel LGI1 missense mutation causes dysfunction in cortical neuronal migration and seizures

Liu, Feng; Du, Chao; Tian, Xin; Ma, Yuanlin; Yin, Yan; Lin, Zijun; Lin, Peijia; Zhou, Ruijiao; Wang, Xuefeng

doi:10.1016/j.brainres.2019.146332

Cited by 7 publications

(13 citation statements)

References 46 publications

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“…Ultimately and mimicking clinical diagnoses of epilepsies using video-electroencephalographic monitoring 2 , 30 , 44 , our electrophysiology-based screening approach successfully identified spontaneous epileptiform activity that was not easily detected in locomotion-based assays. Although simple locomotor readouts have grown popular as seizure assays 69 – 74 , this study emphasizes the scientific rigor necessary to accurately identify epileptic phenotypes in zebrafish and suggests that sole reliance on simple behavioral readouts may lead to misleading conclusions during phenotyping and/or drug discovery efforts.…”

Section: Discussionmentioning

confidence: 96%

Phenotypic analysis of catastrophic childhood epilepsy genes

et al. 2021

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Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

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Section: Discussionmentioning

confidence: 96%

Phenotypic analysis of catastrophic childhood epilepsy genes

et al. 2021

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“…Although simple locomotor readouts have grown popular as seizure assays [69][70][71][72][73][74] , this study emphasizes the rigor necessary to accurately identify epileptic phenotypes in zebrafish and suggests that sole reliance on behavior may lead to misleading conclusions during phenotyping and/or drug discovery efforts.…”

Section: Discussionmentioning

confidence: 97%

Phenotypic analysis of catastrophic childhood epilepsy genes: The Epilepsy Zebrafish Project

Griffin

Carpenter

Liu

et al. 2021

Preprint

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Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. A unifying epilepsy classification scheme was developed based on local field potential recordings and blinded scoring from ~3300 larvae. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

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“…The P43R mutation is likely to cause improper folding of the protein. 45 The other four mutations disrupt intramolecular disulfide bonds, which may be critical in stabilizing the N‐terminal edges of LRR. 9 Several secretion‐defective mutations have been reported to affect the structure of LGI1.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of the P43R mutation in the Lgi1 knockdown zebrafish was used to evaluate its effects on animal motion. 45 Mouse models of familial epilepsy have been recently developed using a transgenic strategy, which re‐expresses the transgenic mutant Lgi1 in homozygous knockout mice (Lgi1 −/−; mutation ). 8 , 27 Transgenic mice are not only valuable for understanding the pathomechanisms of the mutations, but also provide a useful tool to screen for personalized treatments.…”

Section: Discussionmentioning

confidence: 99%

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

Zang

et al. 2021

CNS Neurosci Ther

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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.

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A novel LGI1 missense mutation causes dysfunction in cortical neuronal migration and seizures

Cited by 7 publications

References 46 publications

Phenotypic analysis of catastrophic childhood epilepsy genes

Phenotypic analysis of catastrophic childhood epilepsy genes

Phenotypic analysis of catastrophic childhood epilepsy genes: The Epilepsy Zebrafish Project

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

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