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|Title:||Loss of synaptic Zn2+ transporter function increases risk of febrile seizures|
|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|
|Citation:||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.|
|Subjects:||Cation Transport Proteins|
|Type of Clinical Study or Trial:||Case Control Studies|
|Appears in Collections:||Journal articles|
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