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Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism
Author(s) -
Stergachis Andrew B.,
PujolGiménez 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 Shan,
Rotenberg Alexander,
Hediger Matthias A.,
Rodan Lance H.
Publication year - 2019
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25477
Subject(s) - mechanism (biology) , medicine , epilepsy , missense mutation , excitatory amino acid transporter , endocrinology , glutamate receptor , biology , receptor , mutation , genetics , gene , philosophy , epistemology , psychiatry
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.