# Genetic Modifiers of Childhood Epilepsy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $493,135

## Abstract

Epilepsy is a common neurological that will affect 1 in 26 Americans during their lifetime. Mutations in SCN1A,
encoding the neuronal voltage-gated sodium channel Nav1.1, are the most common genetic cause of epilepsy.
Over 1600 SCN1A mutations have been reported in individuals with epilepsy of varying severity, ranging from
mild febrile seizures to Dravet syndrome, a severe infant-onset epileptic encephalopathy caused by
heterozygous loss-of-function mutations. Dravet syndrome is characterized by a variety of seizure types,
developmental delay and elevated mortality risk. A common feature of monogenic epilepsies is variable
expressivity in individuals carrying the same mutation, suggesting that clinical severity is influenced by genetic
modifiers. Mice with heterozygous deletion of Scn1a (Scn1a+/-) recapitulate core features of Dravet syndrome
phenotypes, including spontaneous seizures and increased mortality risk. Loss of Scn1a results in reduced
sodium current in hippocampal GABAergic interneurons, resulting in failure of inhibition and excitatory/inhibitory
imbalance in the brain. Phenotype severity in Scn1a+/- mice is strongly dependent on strain background. Scn1a+/-
mice on the resistant 129 strain (129.Scn1a+/-) have no overt phenotype and live a normal lifespan. In contrast,
Scn1a+/- mice on a [129xB6]F1 strain (F1.Scn1a+/-) exhibit spontaneous seizures and premature lethality, with
50% dying by 1 month of age. Strain-dependent differences are also evident at the level of neuron subtypes.
GABAergic interneurons isolated from the susceptible F1.Scn1a+/- mice exhibit decreased sodium current density
compared to wildtype littermates, while sodium current density is preserved in interneurons isolated from
129.Scn1a+/- relative to wildtype littermates. This suggests that interneurons from strain 129 compensate for the
loss of Nav1.1, while F1 interneurons do not. Based on the strain-dependent difference in phenotypes at the
whole animal and cellular levels, we hypothesize that genetic modifiers influence Scn1a+/- phenotype severity
due to differences in compensatory capacity among neuronal subtypes in the context of Scn1a heterozygous
deletion. We previously mapped several Dravet survival modifier (Dsm) loci that influence premature lethality of
Scn1a+/- mice. In the current proposal, we will address our hypothesis in three aims. First, we will perform fine
mapping and candidate gene analysis at two Dsm loci on mouse chromosomes 7 and 8. Second, we will perform
single cell RNA-seq analysis to characterize differences in cell composition and gene expression in specific cell
subpopulations during the critical phase of phenotype onset in epilepsy susceptible F1.Scn1a+/- and resistant
129.Scn1a+/- mice. Third, we will evaluate the modifier potential of candidate genes in vivo using transcriptional
modulation to up- and down-regulate candidate gene expression. Results from these studies will identify modifier
genes and pathways that influence phenot...

## Key facts

- **NIH application ID:** 10539313
- **Project number:** 5R01NS084959-09
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jennifer A Kearney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $493,135
- **Award type:** 5
- **Project period:** 2014-09-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539313

## Citation

> US National Institutes of Health, RePORTER application 10539313, Genetic Modifiers of Childhood Epilepsy (5R01NS084959-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10539313. Licensed CC0.

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