Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.

Stergachis, Andrew B; Pujol Gimenez, Jonai; Gyimesi, Gergely; Fuster, Daniel Guido; Albano, Giuseppe; Troxler, Marina; Picker, Jonathan; Rosenberg, Paul A; Bergin, Ann; Peters, Jurriaan; Moufawad El Achkar, Christelle; Harini, Chellamani; Manzi, Shannon; Rotenberg, Alexander; Hediger, Matthias A.; Rodan, Lance H (2019). Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism. Annals of neurology, 85(6), pp. 921-926. Wiley-Blackwell 10.1002/ana.25477

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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 three 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. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Pujol Gimenez, Jonai; Gyimesi, Gergely; Fuster, Daniel Guido; Albano, Giuseppe and Hediger, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0364-5134

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Daniel Guido Fuster

Date Deposited:

15 Jul 2019 15:43

Last Modified:

24 Oct 2019 23:33

Publisher DOI:

10.1002/ana.25477

PubMed ID:

30937933

Uncontrolled Keywords:

Epilepsy Neurogenetics SLC1A2

BORIS DOI:

10.7892/boris.130370

URI:

https://boris.unibe.ch/id/eprint/130370

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