Loss of synaptic Zn2 transporter function increases risk of febrile seizures

MS Hildebrand; AM Phillips; SA Mullen; PA Adlard; K Hardies; JA Damiano; V Wimmer; ST Bellows; JM McMahon; R Burgess; R Hendrickx; S Weckhuysen; A Suls; P De Jonghe; IE Scheffer; S Petrou; SF Berkovic; CA Reid

Journal article

Loss of synaptic Zn2 transporter function increases risk of febrile seizures

MS Hildebrand, AM Phillips, SA Mullen, PA Adlard, K Hardies, JA Damiano, V Wimmer, ST Bellows, JM McMahon, R Burgess, R Hendrickx, S Weckhuysen, A Suls, P De Jonghe, IE Scheffer, S Petrou, SF Berkovic, CA Reid

Scientific Reports | NATURE PORTFOLIO | Published : 2015

DOI: 10.1038/srep17816

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Abstract

Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn2+) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn2+ homeostasis contributes to susceptibility is unknown. Synaptic Zn2+ is co-released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn2+ 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..

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University of Melbourne Researchers

Michael Hildebrand Author

Paul Adlard Author

Verena Wimmer Author

Ingrid Scheffer Author

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

We thank the families for their participation in this study. Elena Aleksoska (Epilepsy Research Centre) is acknowledged for performing genomic DNA extractions. Technical expertise was provided by the Flow Cytometry Facility, MBC, Parkville and the Biometals Facility, MBC, Parkville. We thank Rosie Hartie for help with the imaging experiments. We acknowledge the contribution of the VIB Genetic Service Facility for the genetic follow-up analyses (http://www.vibgeneticservicefacility.be). The Florey Institute of Neuroscience and Mental Health is supported by Victorian State Government infrastructure funds. This work was supported by National Health and Medical Research Council (NHMRC) Program Grant (628952) to S.F.B., S.P. and I.E.S., an Australia Fellowship (466671) to S.F.B, a Practitioner Fellowship (1006110) to I.E.S, a Postdoctoral Training Fellowship to S.A.M, and a Career Development Fellowship (1063799) to M.S.H. C.A.R is supported by a Dowd Fellowship. K.H. is a PhD fellow of the Institute for Science and Technology (IWT)-Flanders and A.S. is a postdoctoral fellow of the FWO.