SCN8A: Variants are linked to multiple neurological conditions, most notably epilepsy and neurodevelopmental disorders.

• Gene Information: The sodium voltage-gated channel alpha subunit 8 (SCN8A) gene encodes the Nav1.6 sodium channel protein, a member of the sodium channel alpha subunit gene family.
• Protein Expression: Nav1.6 is highly expressed in the central nervous system. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons.
• Signaling Pathway: Nav1.6 modulates sodium permeability via sensing membrane potential shifts. Upon depolarization reaching threshold, the sodium channel quickly opens to permit sodium influx, driving further membrane depolarization and action potential generation.
• Therapeutic Inhibition: Therapeutic strategies for SCN8A-related diseases have rapidly diverged into three major approaches: precision small molecules designed to modulate sodium channel activity, antisense nucleic acids intended to reduce expression of pathogenic alleles, and gene therapy aimed at restoring or replacing defective functions.

SCN8A

• The exons 1-27 of mouse Scn8a gene that encode the whole molecule (ATG to STOP codon), including 3’UTR were replaced by human counterparts in B-hSCN8A mice. The promoter and 5’UTR region of the mouse gene were also replaced.
• The human SCN8A expression is driven by human SCN8A promoter, while mouse Scn8a gene transcription and translation will be disrupted.

Strain-specific SCN8A expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hSCN8A mice. Cortex RNA was isolated from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hSCN8A mice (H/H), then cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human SCN8A primers. Human SCN8A mRNA was detectable only in homozygous B-hSCN8A mice but not in wild-type mice.

Protein expression analysis of SCN8A in homozygous B-hSCN8A mice. Various tissue lysates were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hSCN8A mice (H/H), and then analyzed by western blot with anti-SCN8A antibody (Abcam, ab302786). 40 μg total protein was loaded for western blotting analysis. SCN8A protein was detectable in cortex, hippocampus and cerebellum from homozygous B-hSCN8A mice and wild-type C57BL/6 mice, as the antibody was cross-reactive between human and mouse.