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Title: Loss of synaptic Zn2+ transporter function increases risk of febrile seizures
Austin Authors: 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
Affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
School of Biosciences, University of Melbourne, Parkville, Victoria, Australia
Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Division of Neurology, Antwerp University Hospital, Antwerp, Belgium
Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
Issue Date: 9-Dec-2015
Publication information: Scientific Reports 2016; 5: 17816
Abstract: 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.
DOI: 10.1038/srep17816
ORCID: 0000-0002-2311-2174
Journal: Scientific Reports
PubMed URL:
Type: Journal Article
Subjects: Cation Transport Proteins
Seizures, Febrile
Type of Clinical Study or Trial: Case Control Studies
Appears in Collections:Journal articles

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