title: A rat model for LGI1-related epilepsies.
abstract: Mutations of the leucine-rich glioma-inactivated 1 (LGI1) gene cause an autosomal dominant partial epilepsy with auditory features also known as autosomal-dominant lateral temporal lobe epilepsy. LGI1 is also the main antigen present in sera and cerebrospinal fluids of patients with limbic encephalitis and seizures, highlighting its importance in a spectrum of epileptic disorders. LGI1 encodes a neuronal secreted protein, whose brain function is still poorly understood. Here, we generated, by ENU (N-ethyl-N-nitrosourea) mutagenesis, Lgi1-mutant rats carrying a missense mutation (L385R). We found that the L385R mutation prevents the secretion of Lgi1 protein by COS7 transfected cells. However, the L385R-Lgi1 protein was found at low levels in the brains and cultured neurons of Lgi1-mutant rats, suggesting that mutant protein may be destabilized in vivo. Studies on the behavioral phenotype and intracranial electroencephalographic signals from Lgi1-mutant rats recalled several features of the human genetic disorder. We show that homozygous Lgi1-mutant rats (Lgi1(L385R/L385R)) generated early-onset spontaneous epileptic seizures from P10 and died prematurely. Heterozygous Lgi1-mutant rats (Lgi1(+/L385R)) were more susceptible to sound-induced, generalized tonic-clonic seizures than control rats. Audiogenic seizures were suppressed by antiepileptic drugs such as carbamazepine, phenytoin and levetiracetam, which are commonly used to treat partial seizures, but not by the prototypic absence seizure drug, ethosuximide. Our findings provide the first rat model with a missense mutation in Lgi1 gene, an original model complementary to knockout mice. This study revealed that LGI1 disease-causing missense mutations might cause a depletion of the protein in neurons, and not only a failure of Lgi1 secretion.
authors.affiliation: Inserm U975, CRICM, France. stephanie.baulac@upmc.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
authors.forename: Saeko
authors.initials: S
authors.lastname: Ishida
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Morgane
authors.initials: M
authors.lastname: Boillot
authors.forename: Naohiro
authors.initials: N
authors.lastname: Fumoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
authors.forename: Akiko
authors.initials: A
authors.lastname: Takizawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoto
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Akio
authors.initials: A
authors.lastname: Ikeda
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D020195:Epilepsy, Reflex / Q000188:drug therapy / Q000235:genetics; D005013:Ethosuximide / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000077287:Levetiracetam; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011922:Rats, Mutant Strains
chemical_list: D000927:Anticonvulsants; D036341:Intercellular Signaling Peptides and Proteins; C513865:Lgi1 protein, rat; D011506:Proteins; D002220:Carbamazepine; D000077287:Levetiracetam; D005013:Ethosuximide; D010672:Phenytoin; D010889:Piracetam