# Functional Genetics of the Neuronal Sodium Channel Gene SCN8A

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $509,138

## Abstract

Abstract
The SCN8A gene encodes the voltage-gated sodium channel Nav1.6 that is expressed in neurons throughout
the central and peripheral nervous system. Nav1.6 is concentrated at the axon initial segment and nodes of
Ranvier. Mutations of SCN8A affect many aspects of brain and peripheral nerve function. In 2012 we
described the first mutation of SCN8A in a child with early onset epileptic encephalopathy. Since then more
than 150 de novo missense mutations have been identified in this severe form of epilepsy (OMIM # 614558).
Our functional characterization of 10 patient mutations demonstrated that gain-of-function mutations resulting
in channel hyperactivity are the major pathogenic mechanism underlying SCN8A encephalopathy. We
generated a mouse model of the first identified SCN8A mutation, p.Asn1768Asp, that is widely used for
evaluation of therapeutic interventions. We will use this model to isolate a recently discovered genetic modifier
that results in complete rescue of seizures and sudden death. We will also assess the pre-clinical
effectiveness of antisense oligonucleotides and RNAi reagents that suppress the expression of the dominant
SCN8A mutation in the N1768D mouse model. To explore the basis for the severe hypotonia associated with
many SCN8A mutations, we have generated a new conditional mouse model with CRE-dependent expression
of the more severe patient mutation p.Arg1872Trp. We will use this new model to examine the role of mutant
Nav1.6 in specific subsets of neurons at varying stages of development. This conditional model will also be
used to directly test the contribution of cardiac expression of hyperactive Nav1.6 to the risk of sudden death.
These studies will provide new knowledge regarding pathogenic mechanisms underlying SCN8A
encephalopathy, and will test the effectiveness of gene suppression as a therapeutic intervention for this
severe neurological disorder.

## Key facts

- **NIH application ID:** 10329905
- **Project number:** 5R01NS034509-25
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MIRIAM H MEISLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $509,138
- **Award type:** 5
- **Project period:** 1996-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329905

## Citation

> US National Institutes of Health, RePORTER application 10329905, Functional Genetics of the Neuronal Sodium Channel Gene SCN8A (5R01NS034509-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329905. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*