PUBLICATION
A novel LGI1 missense mutation causes dysfunction in cortical neuronal migration and seizures
- Authors
- Liu, F., Du, C., Tian, X., Ma, Y., Zhao, B., Yan, Y., Lin, Z., Lin, P., Zhou, R., Wang, X.
- ID
- ZDB-PUB-190714-7
- Date
- 2019
- Source
- Brain research 1721: 146332 (Journal)
- Registered Authors
- Keywords
- Epilepsy, LGI1, Mutation, Neuronal migration
- MeSH Terms
-
- Adult
- Asian People
- Epilepsies, Partial/genetics*
- Epilepsies, Partial/pathology*
- Epilepsy, Temporal Lobe/genetics
- Epilepsy, Temporal Lobe/pathology
- Exons/genetics
- Family
- Female
- Genotype
- Heterozygote
- Humans
- Intracellular Signaling Peptides and Proteins/genetics*
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Middle Aged
- Mutation/genetics
- Mutation, Missense/genetics
- Pedigree
- Phenotype
- Seizures/genetics
- Seizures/pathology
- PubMed
- 31301272 Full text @ Brain Res.
Citation
Liu, F., Du, C., Tian, X., Ma, Y., Zhao, B., Yan, Y., Lin, Z., Lin, P., Zhou, R., Wang, X. (2019) A novel LGI1 missense mutation causes dysfunction in cortical neuronal migration and seizures. Brain research. 1721:146332.
Abstract
Background To explore the causative genes and pathogenesis of autosomal dominant partial epilepsy with auditory features in a large Chinese family that includes 7 patients over four generations.
Methods We used targeted exome sequencing and Sanger sequencing to validate the mutation. Zebrafish were used to explore the epileptic behavior caused by the mutation. Primary cortical neuronal culturing and in utero electroporation were used to observe the influences of the mutation on neuronal polarity and migration.
Results We report the identification of a novel missense mutation, c.128C>G (p. Pro43Arg), in exon 1 of LGI1. The heterozygous missense mutation, which cosegregated with the syndrome, was absent in 300 unrelated and matched-ancestor controls. The mutation inhibited the secretion of LGI1 and could not rescue the hyperactivity caused by lgi1a knockdown in zebrafish. In vitro, mutant LGI1 interrupts normal cell polarity. In agreement with these findings, dysfunctional cortical neuron migration was observed using in utero electroporation technology, which is reminiscent of the subtle structural changes in the lateral temporal region observed in the proband of this family.
Conclusion Our findings enrich the spectrum of LGI1 mutations and support the pathogenicity of the mutation. Furthermore, additional information regarding the role of LGI1 in the development of temporal lobe epilepsy was elucidated, and a potential relationship was established between cortical neuronal migration dysfunction and autosomal dominant partial epilepsy with auditory features.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping