SCN1A gene

The SCN1A gene (SCN1A stands for: Sodium Voltage-Gated Channel Alpha Subunit 1) is a protein-coding gene located on chromosome 2q24.3. An important paralog of this gene is SCN2A. Alternative splicing leads to several transcript variants.

Voltage-gated sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel consists of a large, pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene codes for the alpha subunit of the sodium channel, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy.

The encoded protein V mediates the voltage-dependent sodium ion permeability of excitable membranes. The protein adopts open or closed conformations in response to the voltage difference across the membrane and forms a sodium-selective channel through which Na(+) ions can pass depending on their electrochemical gradient (Lossin C et al. 2003). Plays a key role in the brain by probably regulating the timing of neurotransmitter release in neurons. Involved in the sensory perception of mechanical pain: activation in somatosensory neurons triggers pain without neurogenic inflammation and leads to hypersensitivity to mechanical but not thermal stimuli.

Diseases associated with SCN1A include Dravet syndrome (Chilcott E et al. 2022), a form of epilepsy, and familial hemiplegic migraine. The associative occurrence of this neurological disorder with Melkersson-Rosenthal syndrome is noteworthy.

Mode of inheritance/genetics: SCN1A seizure disorders are inherited in an autosomal dominant manner. A proband with SCN1A seizure disorder may have an inherited or a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants varies by phenotype: the percentage of probands with SCN1A seizure disorder and an affected parent decreases with increasing severity of the phenotype in probands; thus, most SCN1A-related severe myoclonic epilepsies of infancy (SCN1A-SMEI) and ICE-GTC are the result of a de novo pathogenic variant. Each child of a person with SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% due to lower penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant is known in the family.

Voltage-gated sodium channels (NaV) are responsible for the initiation and propagation of action potentials in excitable cells, including nerve, muscle and neuroendocrine cell types. They are also expressed at low levels in non-excitable cells, although their physiological role is unclear.

1. Chilcott E et al. (2022) Genetic therapeutic advancements for Dravet Syndrome. Epilepsy Behav132:108741.
2. de Lange IM et al. (2019) Outcomes and comorbidities of SCN1A-related seizure disorders. Epilepsy Behav 90:252-259.
3. Lossin C et al. (2003) Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A. J Neurosci 23:11289-95.