| A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. | |
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MedLine Citation:
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PMID: 11166117 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Na(v)1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24. |
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Authors:
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J A Kearney; N W Plummer; M R Smith; J Kapur; T R Cummins; S G Waxman; A L Goldin; M H Meisler |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Neuroscience Volume: 102 ISSN: 0306-4522 ISO Abbreviation: Neuroscience Publication Date: 2001 |
Date Detail:
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Created Date: 2001-02-22 Completed Date: 2001-05-03 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 7605074 Medline TA: Neuroscience Country: United States |
Other Details:
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Languages: eng Pagination: 307-17 Citation Subset: IM |
Affiliation:
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Department of Human Genetics, University of Michigan, 4909 Buhl Box 0618, Ann Arbor, MI 48109-0618, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Behavior, Animal Cells, Cultured Disease Models, Animal Disease Progression Electroencephalography Epilepsy / genetics*, physiopathology* Hippocampus / metabolism, pathology, physiopathology Mice Mice, Transgenic Mutation* Nerve Tissue Proteins / genetics*, metabolism Neurons / cytology, metabolism Oocytes / cytology, metabolism Organ Specificity Patch-Clamp Techniques Sodium / metabolism Sodium Channels / genetics*, metabolism Stereotyped Behavior* Survival Rate Transfection Transgenes Xenopus |
| Grant Support | |
ID/Acronym/Agency:
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NS26729/NS/NINDS NIH HHS; NS34509/NS/NINDS NIH HHS; T32 HD07505/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nerve Tissue Proteins; 0/Sodium Channels; 0/sodium channel, voltage-gated, type II, alpha 1 subunit; 7440-23-5/Sodium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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