Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.
basic_science · Level V
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- Record sourced from PubMed, PMID 30937933.
- Also identified by DOI 10.1002/ana.25477 and PMC identifier 6800210.
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Abstract
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.
Medical subject headings
- Epilepsy, Generalized
- Excitatory Amino Acid Transporter 2
- Genetic Variation