SCN1A

Variants in SCN1A causes the most common cause of monogenic epilepsy, Dravet syndrome, characterized by early-onset, treatment-resistant seizures and developmental delay. SCN1A is also linked to several other disorders including autism spectrum disorder and hemiplegic migraine. The gene encodes an ion channel that mediates the firing of action potentials, the electrical signals that enable neurons to communicate in the brain.

Biological Function

SCN1A encodes the pore-forming alpha subunit of the NaV1.1, a voltage-gated sodium channel that is widely expressed in the brain.
Haploinsufficiency of SCN1A, usually due to loss-of-function variants, leads to seizures and hyperexcitability in animal and cellular models.
SCN1A/NaV1.1 dysfunction in interneurons (inhibitory neurons) has been highlighted as an important contributor to seizures, but other potential disease mechanisms may also be important.

Research at Northwestern

Research from the Carvill Lab at Northwestern University has uncovered the critical role of alternative splicing in the SCN1A gene. Their work focuses on how specific regulatory elements, known as "poison exons," influence gene expression and contribute to neurological conditions.

Key publications include:

Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies.
Gemma L Carvill, Krysta L Engel, Aishwarya Ramamurthy, J Nicholas Cochran, Jolien Roovers, Hannah Stamberger, Nicholas Lim, Amy L Schneider, Georgie Hollingsworth, Dylan H Holder, Brigid M Regan, James Lawlor, Lieven Lagae, Berten Ceulemans, E Martina Bebin, John Nguyen; EuroEPINOMICS Rare Epilepsy Syndrome, Myoclonic-Astatic Epilepsy, and Dravet Working Group; Gregory S Barsh, Sarah Weckhuysen, Miriam Meisler, Samuel F Berkovic, Peter De Jonghe, Ingrid E Scheffer, Richard M Myers, Gregory M Cooper, Heather C Mefford.
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Antisense oligonucleotide therapy rescues aberrant splicing in SCN1A-associated epilepsies.
Sheng Tang, Hannah Stamberger, Jeffrey D Calhoun, Sarah Weckhuysen, Gemma L Carvill.
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Long-read sequencing and profiling of RNA-binding proteins reveals the pathogenic mechanism of aberrant splicing of an SCN1A poison exon in epilepsy.
Hannah C Happ, Patricia N Schneider, Jung Hwa Hong, Eleanor Goes, Masha Bandouil, Carina G Biar, Aishwarya Ramamurthy, Fairlie Reese, Krysta Engel, Sarah Weckhuysen, Ingrid E Scheffer, Heather C Mefford, Jeffrey D Calhoun, Gemma L Carvill.
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Clinical Trials

Multiple clinical trials are currently underway for Dravet syndrome and other SCN1A-related disorders, including studies exploring the use of antisense oligonucleotides targeting poison exons to reduce seizures.
View trials on ClinicalTrials.gov
Additional support, education, and resources for patients and families are available through the
Dravet Syndrome Foundation