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Title: A rat model for LGI1-related epilepsies.
Authors: Baulac, Stéphanie
Ishida, Saeko
Mashimo, Tomoji  KAKEN_id
Boillot, Morgane
Fumoto, Naohiro
Kuwamura, Mitsuru
Ohno, Yukihiro
Takizawa, Akiko
Aoto, Toshihiro
Ueda, Masatsugu
Ikeda, Akio  kyouindb  KAKEN_id  orcid (unconfirmed)
LeGuern, Eric
Takahashi, Ryosuke  kyouindb  KAKEN_id
Serikawa, Tadao
Author's alias: 真下, 知士
Issue Date: 15-May-2012
Publisher: Oxford University Press
Journal title: Human molecular genetics
Volume: 21
Issue: 16
Start page: 3546
End page: 3557
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.
Rights: © The Author 2012. Published by Oxford University Press
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1093/hmg/dds184
PubMed ID: 22589250
Appears in Collections:Journal Articles

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