Two novel epilepsy-linked mutations leading to a loss of function of LGI1

Background: Mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been implicated in autosomal dominant lateral temporal epilepsy. Objective: To describe the clinical and genetic findings in 2 families with autosomal dominant lateral temporal epilepsy and the functional consequences of 2 novel mutations in LGI1. Design: Clinical, genetic, and functional investigations. Setting: University hospital. Patients: Two French families with autosomal dominant lateral temporal epilepsy. Main Outcome Measure: Mutation analysis. Results: Two novel disease-linked mutations, p.Leu232Pro and c.431 + 1G > A, were identified in LGI1. We demonstrated that the c.431 + 1G > A mutation causes the deletion of exons 3 and 4 of the LGI1 transcript and showed that the p.Leu232Pro mutation dramatically decreases secretion of the mutant protein by mammalian cells. Conclusion: Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function.