Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
04
12
2018
revised:
11
02
2019
accepted:
31
03
2019
pubmed:
3
4
2019
medline:
31
3
2020
entrez:
3
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30937933
doi: 10.1002/ana.25477
pmc: PMC6800210
mid: NIHMS1054668
doi:
Substances chimiques
Excitatory Amino Acid Transporter 2
0
SLC1A2 protein, human
0
Ceftriaxone
75J73V1629
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
921-926Subventions
Organisme : NINDS NIH HHS
ID : R01 NS066019
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH104318
Pays : United States
Organisme : Swiss National Science Foundation
ID : 31003A_156376
Pays : Switzerland
Organisme : Marie Curie Actions International Fellowship Program TransCure
Pays : International
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Informations de copyright
© 2019 American Neurological Association.
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