Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/44511
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Type: Journal article
Title: NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity
Author: Dibbens, L.
Ekberg, J.
Taylor, I.
Hodgson, B.
Conroy, S.
Lensink, I.
Kumar, S.
Zielinski, M.
Harkin, L.
Sutherland, G.
Adams, D.
Berkovic, S.
Scheffer, I.
Mulley, J.
Poronnik, P.
Citation: Genes, Brain and Behavior, 2007; 6(8):750-755
Publisher: Blackwell Munksgaard
Issue Date: 2007
ISSN: 1601-1848
1601-183X
Statement of
Responsibility: 
L. M. Dibbens, J. Ekberg, I. Taylor, B. L. Hodgson, S.-J. Conroy, I. L. Lensink, S. Kumar, M. A. Zielinski, L. A. Harkin, G. R. Sutherland, D. J. Adams, S. F. Berkovic, I. E. Scheffer, J. C. Mulley and P. Poronnik
Abstract: Photosensitive seizures occur most commonly in childhood and adolescence, usually as a manifestation of complex idiopathic generalized epilepsies (IGEs). Molecular mechanisms underlying this condition are yet to be determined because no susceptibility genes have been identified. The NEDD4-2 (Neuronally Expressed Developmentally Downregulated 4) gene encodes a ubiquitin protein ligase proposed to regulate cell surface levels of several ion channels, receptors and transporters involved in regulating neuronal excitability, including voltage-gated sodium channels (VGSCs), the most clinically relevant of the epilepsy genes. The regulation of NEDD4-2 in vivo involves complex interactions with accessory proteins in a cell type specific manner. We screened NEDD4-2 for mutations in a cohort of 253 families with IGEs. We identified three NEDD4-2 missense changes in highly conserved residues; S233L, E271A and H515P in families with photosensitive generalized epilepsy. The NEDD4-2 variants were as effective as wild-type NEDD4-2 in downregulating the VGSC subtype Nav1.2 when assessed in the Xenopus oocyte heterologous expression system showing that the direct interaction with the ion channel was not altered by these variants. These data raise the possibility that photosensitive epilepsy may arise from defective interaction of NEDD4-2 with as yet unidentified accessory or target proteins.
Keywords: Chromosomes, Human, Pair 18; Humans; Epilepsy, Generalized; Epilepsy, Reflex; Genetic Predisposition to Disease; Ubiquitin-Protein Ligases; Sodium Channels; Case-Control Studies; Cohort Studies; Pedigree; Ion Channel Gating; Sequence Deletion; Sequence Homology, Amino Acid; Mutation, Missense; Female; Male; Endosomal Sorting Complexes Required for Transport
Description: The definitive version is available at www.blackwell-synergy.com
RMID: 0020073461
DOI: 10.1111/j.1601-183X.2007.00305.x
Appears in Collections:Paediatrics publications

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