Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism

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 locali...

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Bibliographic Details
Published in:Annals of neurology 2019-06, Vol.85 (6), p.921-926
Main Authors: Stergachis, Andrew B., Pujol‐Giménez, Jonai, Gyimesi, Gergely, Fuster, Daniel, Albano, Giusppe, Troxler, Marina, Picker, Jonathan, Rosenberg, Paul A., Bergin, Ann, Peters, Jurriaan, El Achkar, Christelle Moufawad, Harini, Chellamani, Manzi, Shannon, Rotenberg, Alexander, Hediger, Matthias A., Rodan, Lance H.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Ceftriaxone
Ceftriaxone - therapeutic use
Child, Preschool
Encephalopathy
Epilepsy
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
Localization
Male
Protein Structure, Secondary
Synapses
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Description
Summary: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.
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.25477