EpilepsiaNov 3, 2020

The gene Gabra2 changes how Scn8a-related brain disease affects mice

Updated Feb 3, 2026

Abstract

A major genetic factor on chromosome 5 is associated with seizure onset and lifespan in mice with SCN8A mutations.

The gene, located on chromosome 5, is identified as a significant modifier of seizure-related phenotypes in mice carrying the SCN8A-R1872W mutation.
A splice site mutation in the C57BL/6J strain reduces the expression of Gabra2, which encodes a key subunit of a receptor that inhibits brain activity.
Carrying the wild-type allele of Gabra2 from the SJL/J strain is linked to delayed seizure onset and increased lifespan in SCN8A mutant mice.
Other genetic modifiers influencing seizure severity were found in both F1 and F2 crosses, suggesting complexity in the genetic landscape of .

Simplified

OBJECTIVE: is a developmental epileptic encephalopathy typically caused by de novo gain-of-function mutations in Na1.6. Severely affected individuals exhibit refractory seizures, developmental delay, cognitive disabilities, movement disorders, and elevated risk of sudden death. Patients with the identical SCN8A variant can differ in clinical course, suggesting a role for modifier genes in determining disease severity. The identification of genetic modifiers contributes to understanding disease pathogenesis and suggesting therapeutic interventions. v

METHODS: We generated F1 and F2 crosses between inbred mouse strains and mice carrying the human pathogenic variants SCN8A-R1872W and SCN8A-N1768D. Quantitative trait locus (QTL) analysis of seizure-related phenotypes was used for chromosomal mapping of modifier loci.

RESULTS: In an F2 cross between strain SJL/J and C57BL/6J mice carrying the patient mutation R1872W, we identified a major QTL on chromosome 5 containing the gene. Strain C57BL/6J carries a splice site mutation that reduces expression of Gabra2, encoding the α2 subunit of the aminobutyric acid type A receptor. The protective wild-type allele of Gabra2 from strain SJL/J delays the age at seizure onset and extends life span of the Scn8a mutant mice. Additional Scn8a modifiers were observed in the F2 cross and in an F1 cross with strain C3HeB/FeJ.

SIGNIFICANCE: These studies demonstrate that the SJL/J strain carries multiple modifiers with protective effects against seizures induced by gain-of-function mutations in Scn8a. Homozygosity for the hypomorphic variant of Gabra2 in strain C57BL/6J is associated with early seizure onset and short life span. GABRA2 is a potential therapeutic target for SCN8A encephalopathy.

Key numbers

66 days

Survival Increase

Median lifespan of mutants carrying the protective allele.

40 to 110 days

Seizure Onset Delay

Age at seizure onset for with protective variants.

4.5×

Transcript Abundance Increase

Comparison of transcript levels between strains.

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Abstract

Key numbers

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