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

• DOI: 10.1038/srep17816
• Publication Date: 2015-12-09T10:15:31Z
• Authors: Michael S. Hildeb...; A. Marie Phillips; Saul A. Mullen; Paul A. Adlard; Katia Hardies; John A. Damiano; Verena Wimmer; Susannah T. Bellows; Jacinta M. McMahon; Rosemary Burgess; Rik Hendrickx; Sarah Weckhuysen; Arvid Suls; Peter De Jonghe; Ingrid E. Scheffer; Steven Petrou; Samuel F. Berkovic; Christopher A. Reid
• Keywords: Homeostasis

Abstract Febrile seizures (FS) are the most common seizure syndrome and potentially a prelude to more severe epilepsy. Although zinc (Zn 2+ ) metabolism has previously been implicated in FS, whether or not variation proteins essential for Zn homeostasis contributes susceptibility is unknown. Synaptic co-released with glutamate modulates neuronal excitability. SLC30A3 encodes transporter 3 (ZNT3), which primarily responsible moving into synaptic vesicles. Here we sequenced discovered rare variant (c.892C > T; p.R298C) enriched FS populations but absent population-matched controls. Functional analysis revealed significant loss-of-function of mutated protein resulting from trafficking deficit. Furthermore, mice null ZnT3 were sensitive than wild-type hyperthermia-induced that model FS. Together our data suggest reduced increases risk broadly support idea impaired can contribute hyperexcitability.