Preprint maps opposing transcriptional programmes in SCN8A gain- and loss-of-function epilepsy

A preprint posted to bioRxiv (not yet peer-reviewed) addresses a long-standing problem in SCN8A-related epilepsy research: pathogenic variants in SCN8A — which encodes the voltage-gated sodium channel NaV1.6 — cause disease through either gain-of-function (GoF) or loss-of-function (LoF) mechanisms, yet the downstream cellular and transcriptional consequences of each direction have been difficult to disentangle because they typically involve different genetic backgrounds.

The authors constructed an isogenic Scn8a allelic series in mice in which a cis-acting modifier produces stepwise reductions in NaV1.6 protein levels on the same N1768D pathogenic background, allowing GoF, rescued, and LoF states to be compared on a shared genetic context. Hippocampal transcriptomes were profiled and pathway-level inference applied. The study finds that GoF and LoF states are associated with distinct, opposing transcriptional programmes — a result that could inform future stratification of patients for therapeutic approaches, given that treatments appropriate for one functional class may be contraindicated in the other.

SCN8A variants are a recognised cause of DEE (developmental and epileptic encephalopathy), a group of severe childhood epilepsies. The mechanistic distinction between GoF and LoF is clinically meaningful because sodium channel blockers may worsen LoF epilepsies while benefiting GoF epilepsies, and vice versa.

As a preprint, this work has not been peer-reviewed.