Loss of synaptic Zn2+ transporter function increases risk of febrile seizures
AuthorHildebrand, MS; Phillips, AM; Mullen, SA; Adlard, PA; Hardies, K; Damiano, JA; Wimmer, V; Bellows, ST; McMahon, JM; Burgess, R; ...
Source TitleScientific Reports
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sAdlard, Paul; Phillips, Alison; Mullen, Saul; Petrou, Steven; Scheffer, Ingrid; Hildebrand, Michael; Damiano, John; Bellows, Susannah; MCMAHON, JACINTA; Berkovic, Samuel; ...
AffiliationFlorey Department of Neuroscience and Mental Health
Education Unit, MDHS
Medicine (Austin & Northern Health)
Anatomy and Neuroscience
School of BioSciences
Document TypeJournal Article
CitationsHildebrand, M. S., Phillips, A. M., Mullen, S. A., Adlard, P. A., Hardies, K., Damiano, J. A., Wimmer, V., Bellows, S. T., McMahon, J. M., Burgess, R., Hendrickx, R., Weckhuysen, S., Suls, A., De Jonghe, P., Scheffer, I. E., Petrou, S., Berkovic, S. F. & Reid, C. A. (2015). Loss of synaptic Zn2+ transporter function increases risk of febrile seizures. SCIENTIFIC REPORTS, 5 (1), https://doi.org/10.1038/srep17816.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673435
Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn(2+)) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn(2+) homeostasis contributes to susceptibility is unknown. Synaptic Zn(2+) is co-released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn(2+) into synaptic vesicles. Here we sequenced SLC30A3 and discovered a rare variant (c.892C > T; p.R298C) enriched in FS populations but absent in population-matched controls. Functional analysis revealed a significant loss-of-function of the mutated protein resulting from a trafficking deficit. Furthermore, mice null for ZnT3 were more sensitive than wild-type to hyperthermia-induced seizures that model FS. Together our data suggest that reduced synaptic Zn(2+) increases the risk of FS and more broadly support the idea that impaired synaptic Zn(2+) homeostasis can contribute to neuronal hyperexcitability.
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Publisher licenceCC BY
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