2. Academic Validation
  3. Loss of synaptic Zn2+ transporter function increases risk of febrile seizures

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

  • Sci Rep. 2015 Dec 9;5:17816. doi: 10.1038/srep17816.
Michael S Hildebrand 1,  A Marie Phillips 2 3,  Saul A Mullen 2,  Paul A Adlard 2,  Katia Hardies 4 5,  John A Damiano 1,  Verena Wimmer 2,  Susannah T Bellows 1,  Jacinta M McMahon 1,  Rosemary Burgess 1,  Rik Hendrickx 4,  Sarah Weckhuysen 4 5,  Arvid Suls 4 5,  Peter De Jonghe 4 5 6,  Ingrid E Scheffer 1 2 7,  Steven Petrou 2,  Samuel F Berkovic 1,  Christopher A Reid 2
Affiliations

Affiliations

  • 1 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
  • 2 The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
  • 3 School of Biosciences, University of Melbourne, Parkville 3052, Australia.
  • 4 Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.
  • 5 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
  • 6 Division of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 7 Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville 3052, Victoria, Australia.
PMID: 26647834 DOI: 10.1038/srep17816
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.

Figures