title: Loss of synaptic Zn2+ transporter function increases risk of febrile seizures.
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.
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.|School of Biosciences, University of Melbourne, Parkville 3052, Australia.
authors.forename: A Marie
authors.initials: AM
authors.lastname: Phillips
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
authors.forename: Saul A
authors.initials: SA
authors.lastname: Mullen
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
authors.forename: Verena
authors.initials: V
authors.lastname: Wimmer
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Susannah T
authors.initials: ST
authors.lastname: Bellows
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burgess
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Hendrickx
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.|Division of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.|The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville 3052, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D051381:Rats; D012306:Risk; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C102806:SLC30A3 protein, human; D015032:Zinc