Spontaneous seizures and elevated seizure susceptibility in response to somatic mutation of sodium channel Scn8a in the mouse

Abstract De novo mutations of neuronal sodium channels are responsible for ~5% of developmental and epileptic encephalopathies, but the role of somatic mutation of these genes in adult-onset epilepsy is not known. We evaluated the role of post-zygotic somatic mutation by adult activation of a condit...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 2021-05, Vol.30 (10), p.902-907
Main Authors: Yu, Wenxi, Smolen, Corrine E, Hill, Sophie F, Meisler, Miriam H
Format: Article
Language:English
Subjects:
Action Potentials - genetics
Alleles
Animals
Disease Models, Animal
Epilepsy - genetics
Epilepsy - physiopathology
Gene Expression Regulation - drug effects
Heterozygote
Humans
Mice
Mutation - genetics
NAV1.6 Voltage-Gated Sodium Channel - genetics
Neurons - metabolism
Neurons - pathology
Seizures - genetics
Seizures - pathology
Tamoxifen - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract De novo mutations of neuronal sodium channels are responsible for ~5% of developmental and epileptic encephalopathies, but the role of somatic mutation of these genes in adult-onset epilepsy is not known. We evaluated the role of post-zygotic somatic mutation by adult activation of a conditional allele of the pathogenic variant Scn8aR1872W in the mouse. After activation of CAG-Cre-ER by tamoxifen, the mutant transcript was expressed throughout the brain at a level proportional to tamoxifen dose. The threshold for generation of spontaneous seizures was reached when the proportion of mutant transcript reached 8% of total Scn8a transcript, equivalent to expression of the epileptogenic variant in 16% of heterozygous neurons. Expression below this level did not result in spontaneous seizures, but did increase susceptibility to seizure induction by kainate or auditory stimulation. The relatively high threshold for spontaneous seizures indicates that somatic mutation of sodium channels is unlikely to contribute to the elevated incidence of epilepsy in the elderly population. However, somatic mutation could increase susceptibility to other seizure stimuli.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddab092