Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism

Ann Neurol. 2019 Jun;85(6):921-926. doi: 10.1002/ana.25477. Epub 2019 Apr 26.


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 3 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. ANN NEUROL 2019;85:921-926.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Ceftriaxone / therapeutic use
  • Child, Preschool
  • Epilepsy, Generalized / diagnosis*
  • Epilepsy, Generalized / drug therapy
  • Epilepsy, Generalized / genetics*
  • Excitatory Amino Acid Transporter 2 / chemistry
  • Excitatory Amino Acid Transporter 2 / genetics*
  • Female
  • Genetic Variation / genetics*
  • HEK293 Cells
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Protein Structure, Secondary


  • Excitatory Amino Acid Transporter 2
  • SLC1A2 protein, human
  • Ceftriaxone