Sodium channel SCN8A: mapping of a genetic modifier
Abstract number :
8
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2020
Submission ID :
2422357
Source :
www.aesnet.org
Presentation date :
12/5/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Wenxi Yu, University of Michigan; Sophie Hill - University of Michigan; James Xenakis - University of North Carolina at Chapel Hill; Fernando Pardo-Manuel de Villena - University of North Carolina at Chapel Hill; Jacy Wagnon - Ohio State University; Miria
Rationale:
SCN8A encodes the voltage-gated sodium channel Nav1.6, which controls the initiation and propagation of action potentials in neurons. De novo mutations of SCN8A have been reported in patients with a spectrum of clinical phenotypes, the most severe of which is Developmental and Epileptic Encephalopathy (DEE) (OMIM #614558). Patients with identical pathogenic variants can exhibit different clinical courses, suggesting that gene interactions play a role in determining the severity of disease. The identification of genetic modifiers of SCN8A epilepsy will benefit the understand of the pathophysiological mechanism underlying DEE and provide insight into potential therapeutic methods.
Method:
We conducted crosses between inbred strains. Quantitative trait locus (QTL) analysis was performed on seizure-related phenotypes for the identification of candidate modifier genes.
Results:
In an F2 cross between the mutant C57BL/6J.Scn8a-R1872W/+ (Lenk et al, Ann. Neurol. 2020) and strain SJL/J, we found that strain SJL/J contributes multiple modifiers that influence the survival of mutant mice. The SJL/J allele of the major modifier delays the age of seizure onset and extends life span of mutant mice.
Conclusion:
We have identified a candidate modifier gene of SCN8A epilepsy. The modifier gene encodes a druggable target, which provides therapeutic implications for treatment of DEE.
Funding:
:NIH (NINDS) R01 NS34509
Basic Mechanisms