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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Baulac S,Ishida S,Mashimo T,Boillot M,Fumoto N,Kuwamura M,Ohno Y,Takizawa A,Aoto T,Ueda M,Ikeda A,LeGuern E,Takahashi R,Serikawa Tdoi
10.1093/hmg/dds184subject
Has Abstractpub_date
2012-08-15 00:00:00pages
3546-57issue
16eissn
0964-6906issn
1460-2083pii
dds184journal_volume
21pub_type
杂志文章abstract::Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted and the Y chromosome gradually lost its non-essential genetic functions. This model was or...
journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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更新日期:1999-07-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:1992-09-01 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr504
更新日期:2012-02-15 00:00:00
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journal_title:Human molecular genetics
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pub_type: 杂志文章,meta分析
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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更新日期:2008-11-01 00:00:00
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journal_title:Human molecular genetics
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更新日期:2014-02-15 00:00:00
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journal_title:Human molecular genetics
pub_type: 杂志文章,评审
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journal_title:Human molecular genetics
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