SCN1A encodes Nav1.1, a voltage-gated sodium channel alpha subunit expressed predominantly in inhibitory GABAergic interneurons throughout the central nervous system. Pathogenic variants in SCN1A are the leading genetic cause of Dravet syndrome, accounting for ~70-80% of cases. The gene is also associated with genetic epilepsy with febrile seizures plus (GEFS+), febrile seizures, and other epilepsy phenotypes.
SCN1A is one of the most commonly tested genes in pediatric epilepsy, and the discovery of SCN1A variants in a patient with early-onset seizures has become nearly diagnostic for Dravet syndrome[@scn1a2018].
| Property | Value |
|---|---|
| Gene Symbol | SCN1A |
| Chromosomal Location | 2q24.3 |
| Genomic Coordinates | chr2:165,990,000-166,100,000 (GRCh38) |
| Gene Length | ~190 kb |
| Number of Exons | 26 coding exons |
| Transcript Length | ~7.2 kb coding sequence |
| Protein Length | 2,009 amino acids |
| Protein Class | Voltage-gated sodium channel alpha subunit |
| Expression | Brain (neurons, particularly GABAergic interneurons), heart |
| OMIM | 182389 |
| UniProt | P35499 |
Nav1.1 is composed of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6):
Nav1.1 contributes to the upstroke of the action potential in neurons, particularly in inhibitory interneurons. Unlike channels in excitatory neurons (where Nav1.2 and Nav1.6 dominate), Nav1.1's kinetics and localization make it particularly critical for the sustained firing of fast-spiking interneurons that regulate circuit excitability.
The channel operates in three states:
Inhibitory interneurons rely on Nav1.1 for rapid, sustained firing that provides feedforward and feedback inhibition. Loss of Nav1.1 reduces this inhibitory drive, leading to hyperexcitable circuits.
Dravet syndrome is fundamentally a loss-of-function disorder. Over 1,000 pathogenic variants have been identified, all resulting in reduced functional Nav1.1 channels:
The key paradox: despite being expressed throughout the brain, SCN1A loss preferentially affects GABAergic interneurons rather than excitatory pyramidal neurons. This "interneuronopathy" model explains why SCN1A variants cause epilepsy rather than a channelopathy affecting motor or sensory function.
The specificity of Nav1.1 for interneurons likely reflects:
| Disorder | Variant Type | Inheritance | Percentage of Cases |
|---|---|---|---|
| Dravet syndrome | Missense, nonsense, splice, large del | De novo (80%) | ~70-80% of DS cases |
| GEFS+ (Genetic epilepsy with febrile seizures plus) | Missense | Autosomal dominant | ~10-20% of GEFS+ |
| Febrile seizures (isolated) | Missense | Autosomal dominant | <5% |
| Intractable childhood epilepsy with generalized tonic-clonic | Various | De novo | Rare |
Stoke Therapeutics developed STK-001, an allele-specific antisense oligonucleotide that increases SCN1A mRNA and Nav1.1 protein expression from the wild-type allele. By upregulating the normal copy of the gene, STK-001 compensates for the loss of function from the pathogenic variant. See STK-001 clinical trial page and therapeutics hub page.
Encoded Therapeutics developed AAV9-delivered CRISPR-activation (CRISPRa) constructs targeting the SCN1A promoter region to increase endogenous expression. This approach does not require allele specificity — any patient with one functional allele could benefit. See ETX101 clinical trial page.
Full-length SCN1A (~6kb coding) approaches AAV packaging limits. Strategies include:
With ~40% of Dravet patients having missense variants, precision base editing could correct individual point mutations. Beam Therapeutics and academic groups are developing base editors for SCN1A missense mutations.