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dc.contributor.authorSprissler, Ryan S.
dc.contributor.authorWagnon, Jacy L.
dc.contributor.authorBunton-Stasyshyn, Rosie K.
dc.contributor.authorMeisler, Miriam H.
dc.contributor.authorHammer, Michael F.
dc.date.accessioned2017-03-13T23:02:29Z
dc.date.available2017-03-13T23:02:29Z
dc.date.issued2017-02
dc.identifier.citationAltered gene expression profile in a mouse model of SCN8A encephalopathy 2017, 288:134 Experimental Neurologyen
dc.identifier.issn00144886
dc.identifier.doi10.1016/j.expneurol.2016.11.002
dc.identifier.urihttp://hdl.handle.net/10150/622816
dc.description12 month embargo; Available online 9 November 2016en
dc.description.abstractSCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na(v)1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3 fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.
dc.description.sponsorshipNIH [R01 NS34509]; Dravet Syndrome Foundationen
dc.language.isoenen
dc.publisherACADEMIC PRESS INC ELSEVIER SCIENCEen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0014488616303582en
dc.rights© 2016 Elsevier Inc. All rights reserved.en
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectRNA-seqen
dc.subjectTranscriptomeen
dc.subjectSeizureen
dc.subjectEpileptic encephalopathyen
dc.subjectAstrocyteen
dc.subjectGene expressionen
dc.subjectSodium channelen
dc.titleAltered gene expression profile in a mouse model of SCN8A encephalopathyen
dc.typeArticleen
dc.contributor.departmentARL Division of Biotechnology, University of Arizonaen
dc.contributor.departmentDepartment of Neurology, University of Arizonaen
dc.identifier.journalExperimental Neurologyen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal accepted manuscripten
refterms.dateFOA2017-11-10T00:00:00Z
html.description.abstractSCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na(v)1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3 fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.


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