GABRA2 is a genetic modifier of Dravet syndrome in mice

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In previous research reviews we have talked about “Dravet mice” – usually  that means mice which have been engineered to carry a deletion of one copy of the Scn1a gene. These mice exhibit the key features of Dravet syndrome, including febrile and spontaneous seizures, SUDEP, and cognitive and behavioral deficits. But these mice display varying degrees of clinical severity depending on which strain is used – that is, depending on the status of other genes. Humans with Dravet syndrome also display varying degrees of clinical severity, so the question is this – can we discover specific secondary genes that strongly affect the clinical profile?

In the current work, by mixing strains and studying the resulting physiological profiles, the authors were able to identify a candidate for such a gene – Gabra2, the gene that encodes the a2 subunit of the GABAA receptor. A mutation in this gene caused a more severe profile. In a June 2019 research review, we explained that many of the drugs used to treat Dravet syndrome work by interacting with GABAA receptors, so this candidate makes sense.

The mutation caused a reduction in the production of the GABAA protein. The authors were able to make a repair of this mutation in the strain of Dravet mice that carried it. They showed that the repair restored GABAA protein levels. They also found that the repair improved seizure, survival, and neuronal function profiles – confirming Gabra2 as an epilepsy modifier gene.

This is important because identifying modifier genes could lead to the ability to make better predictions about disease course, and therefore better decisions on clinical management. Also, modifier genes and their pathways could provide novel targets for future therapeutics.

Hawkins, N.A. et al. Gabra2 is a genetic modifier of Dravet syndrome in mice. bioRxiv [Epub ahead of print; accepted April 18, 2020]. DOI: 10.1101/2020.04.19.048546.
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