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

Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
2
Department of Nephrology and Hypertension, University Hospital Bern, Inselspital, Bern, Switzerland.
3
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
4
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
5
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
6
Department of Pharmacy, Boston Children's Hospital, Harvard Medical School, Boston, MA.

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.

PMID:
30937933
DOI:
10.1002/ana.25477

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