Altered gene expression profile in a mouse model of SCN8A encephalopathy.
SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. 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.
ARL Division of Biotechnology, University of Arizona, Tucson, AZ 85721, USA.
Ryan S
RS
Sprissler
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Jacy L
JL
Wagnon
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Rosie K
RK
Bunton-Stasyshyn
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: meislerm@umich.edu.
Miriam H
MH
Meisler
ARL Division of Biotechnology, University of Arizona, Tucson, AZ 85721, USA; Department of Neurology, University of Arizona, Tucson, AZ 85721, USA. Electronic address: mfh@email.arizona.edu.
Michael F
MF
Hammer
D000818:Animals; D001927:Brain Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D025341:Principal Component Analysis; D059467:Transcriptome / Q000235:genetics*
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C491046:Scn8a protein, mouse
Astrocyte; Epileptic encephalopathy; Gene expression; RNA-seq; Seizure; Sodium channel; Transcriptome