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.
Keywords: Epilepsy; LGI1; Mutation; Neuronal migration.
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