Sodium channel protein type 8 subunit alpha (SCN8A) (SCN8A)

Sodium channel protein type 8 subunit alpha (SCN8A), commonly referred to as Nav1.6, is a voltage-gated sodium channel essential for the initiation and propagation of action potentials in the central and peripheral nervous systems (UniProt P35498). It is highly concentrated at the axon initial segment and nodes of Ranvier, where it regulates neuronal excitability and high-frequency firing. Pathogenic variants in the SCN8A genomic locus, particularly gain-of-function mutations, are the primary cause of Developmental and Epileptic Encephalopathy type 13 (DEE13), characterized by refractory seizures and developmental delay (OMIM 600702). Therapeutic interventions targeting the SCN8A mutant allele include selective small-molecule inhibitors like NBI-921352 and PRAX-562, which aim to reduce the overactive sodium current, as well as antisense oligonucleotides (ASOs) like PRAX-020 designed to downregulate the expression of the overactive protein (Neurocrine Biosciences; Praxis Precision Medicines). Precision medicine approaches are critical for this target, as non-selective sodium channel blockers may cause off-target effects on other sodium channel subtypes like Nav1.1 or Nav1.5, potentially worsening clinical outcomes.

Other names

Nav1.6CerlMEDEIEE13BFIS5Sodium channel voltage-gated type VIII alpha subunitVoltage-gated sodium channel subunit alpha Nav1.6

Selective inhibition of the Nav1.6 voltage-gated sodium channel, reduction of persistent sodium current, or antisense oligonucleotide-mediated reduction of SCN8A mRNA expression.