Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.

Stergachis, Andrew B; Pujol Gimenez, Jonai; Gyimesi, Gergely; Fuster, Daniel Guido; Albano, Giuseppe; Troxler, Marina; Picker, Jonathan; Rosenberg, Paul A; Bergin, Ann; Peters, Jurriaan; Moufawad El Achkar, Christelle; Harini, Chellamani; Manzi, Shannon; Rotenberg, Alexander; Hediger, Matthias A.; Rodan, Lance H (2019). Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism. Annals of neurology, 85(6), pp. 921-926. Wiley-Blackwell 10.1002/ana.25477

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SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early-onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all three variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild-type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20-month-old SLC1A2-related epilepsy patient with the SLC1A2 modulating agent ceftriaxone did not result in a significant change in daily spasm count. This article is protected by copyright. All rights reserved.

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