In late June 2020, Voskobiynyk et al shared their recent manuscript on bioRxiv (pre-print before peer-review) detailing a novel mouse model of Dravet syndrome that carries the same mutation in a non-coding region as a patient diagnosed with Dravet syndrome. “Non-coding” means that the mutation is not located in an area of the DNA that is used to make the protein product. Several similar mutations in patients with Dravet syndrome were identified by this group and their collaborators previously (Carvill et al 2018), and that work indicated that these mutations increased the inclusion of a “poison exon.” Inclusion of this poison exon into the mRNA introduces a premature stop codon and causes the mRNA to be degraded. Ultimately, this leads to a reduction in production of the Nav1.1 sodium channel. Voskobiynyk et al were able to utilize this mouse model to confirm these mechanisms in a living organism, whereas previous studies had only shown these concepts in cells. They confirmed that this mutation increases usage of the poison exon, and consequently, decreases Nav1.1 protein levels by ~50% in the cortex of mice carrying this mutation. These mice also modeled several Dravet syndrome-like phenotypes, including spontaneous seizure activity, increased premature mortality, and hyperexcitability.

While there are already several mouse models of Dravet syndrome, developing multiple animal models of a disease can help to elucidate different aspects of the disease. This model particularly contributes to our knowledge of how specific types of genetic mutations lead to Dravet syndrome and can be used to study how those mutations affect brain development and the progression of disease. As exciting new genetic approaches to treatment advance, it is important that we continue to understand the various underlying mechanisms that drive Dravet syndrome so therapies can become more targeted.

Voskobiynyk Y. et al. Aberrant regulation of a poison exon caused by a non-coding variant in Scn1a-associated epileptic encephalopathy. bioRxiv [preprint posted June 21,2020). DOI: 10.1101/2020.06.21.163428