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Loss of synaptic Zn²⁺ transporter function increases risk of febrile seizures

Hildebrand, Michael S., Phillips, A. Marie, Mullen, Saul A., Adlard, Paul A., Hardies, Katia, Damiano, John A., Wimmer, Verena, Bellows, Susannah T., McMahon, Jacinta M., Burgess, Rosemary, Hendrickx, Rik, Weckhuysen, Sarah, Suls, Arvid, De Jonghe, Peter, Scheffer, Ingrid E., Petrou, Steven, Berkovic, Samuel F. and Reid, Christopher A. 2015, Loss of synaptic Zn²⁺ transporter function increases risk of febrile seizures, Scientific reports, vol. 5, pp. 1-9, doi: 10.1038/srep17816.

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Title Loss of synaptic Zn²⁺ transporter function increases risk of febrile seizures
Author(s) Hildebrand, Michael S.
Phillips, A. Marie
Mullen, Saul A.
Adlard, Paul A.
Hardies, Katia
Damiano, John A.
Wimmer, Verena
Bellows, Susannah T.
McMahon, Jacinta M.
Burgess, Rosemary
Hendrickx, Rik
Weckhuysen, Sarah
Suls, Arvid
De Jonghe, Peter
Scheffer, Ingrid E.
Petrou, Steven
Berkovic, Samuel F.
Reid, Christopher A.
Journal name Scientific reports
Volume number 5
Article ID 17816
Start page 1
End page 9
Total pages 9
Publisher Nature
Place of publication London, Eng.
Publication date 2015-12-09
ISSN 2045-2322
Keyword(s) Amino Acid Sequence
Animals
Case-Control Studies
Cation Transport Proteins
Cell Line
DNA Mutational Analysis
Genetic Predisposition to Disease
Humans
Inheritance Patterns
Kaplan-Meier Estimate
Mice, Knockout
Molecular Sequence Data
Mutation
Pedigree
Rats
Risk
Seizures, Febrile
Sequence Alignment
Sequence Analysis, DNA
Zinc
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GENERALIZED EPILEPSY
GENETIC EPILEPSY
SODIUM-CHANNEL
MOUSE
EPIDEMIOLOGY
MUTATIONS
CHILDREN
SUBTYPES
NEURONS
Summary 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.
Language eng
DOI 10.1038/srep17816
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2015, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30110660

Document type: Journal Article
Collections: School of Psychology
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.