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  • NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity

    Author(s)
    Dibbens, LM
    Ekberg, J
    Taylor, I
    Hodgson, BL
    Conroy, S-J
    Lensink, IL
    Kumar, S
    Zielinski, MA
    Harkin, LA
    Sutherland, GR
    Adams, DJ
    Berkovic, SF
    Scheffer, IE
    Mulley, JC
    Poronnik, P
    Griffith University Author(s)
    Ekberg, Jenny A.
    Year published
    2007
    Metadata
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    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 ...
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    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.
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    Journal Title
    Genes, Brain and Behavior
    Volume
    6
    Issue
    8
    DOI
    https://doi.org/10.1111/j.1601-183X.2007.00305.x
    Subject
    Biological sciences
    Cell neurochemistry
    Biomedical and clinical sciences
    Psychology
    Publication URI
    http://hdl.handle.net/10072/28099
    Collection
    • Journal articles

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