Abstracts

Rationale: Genetic factors play an increasingly recognized role in idiopathic epilepsies. To this date, a dozen of genes have been linked to monogenic autosomal dominant idiopathic epilepsies. Until recently, human hereditary idiopathic epilepsies were thought to be exclusively channelopathies, since all mutated genes encoded subunits of ion channels (sodium and potassium channels) or neurotransmitter receptor (GABA and acetylcholine receptor). LGI1 (Leucine-rich glioma inactivated 1) gene was the first non-ion channel gene identified in monogenic human idiopathic epilepsy. Mutations in the LGI1 gene are the major cause of autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE referrers to a familial epileptic condition characterized by an age at onset typically in late adolescence, focal and secondarily tonic-clonic generalized seizures with stereotyped auditory auras. Methods: We have investigated the functional consequences of several disease-causing LGI1 missense mutations in mammalian cells in culture. We have demonstrated that they dramatically decrease secretion of the mutant suggesting that LGI1-related epilepsy results from a loss-of-function. We have generated a LGI1-invalidation to model the LGI1 haploinsufficiency in mice. Results: Heterozygote LGI1+/- and homozygous LGI1-/- mice were successfully obtained according to Mendelian expected ratio. LGI1-/- and LGI1+/- mice are undistinguishable from the WT mice at birth. Homozygote LGI1-/- mice exhibit spontaneous seizures starting at P10. Conclusions: We have generated a novel model which might help to clarify the function of the newly identified LGI1 protein in brain development, neuronal excitability and epileptogenesis.