title: NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity.
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 Na(v)1.2 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.
authors.affiliation: Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. leanne.dibbens@cywhs.sa.gov.au
authors.forename: L M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: J
authors.initials: J
authors.lastname: Ekberg
authors.forename: I
authors.initials: I
authors.lastname: Taylor
authors.forename: B L
authors.initials: BL
authors.lastname: Hodgson
authors.forename: S-J
authors.initials: SJ
authors.lastname: Conroy
authors.forename: I L
authors.initials: IL
authors.lastname: Lensink
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: M A
authors.initials: MA
authors.lastname: Zielinski
authors.forename: L A
authors.initials: LA
authors.lastname: Harkin
authors.forename: G R
authors.initials: GR
authors.lastname: Sutherland
authors.forename: D J
authors.initials: DJ
authors.lastname: Adams
authors.forename: S F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: I E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: J C
authors.initials: JC
authors.lastname: Mulley
authors.forename: P
authors.initials: P
authors.lastname: Poronnik
mesh_terms: D016022:Case-Control Studies; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015331:Cohort Studies; D056827:Endosomal Sorting Complexes Required for Transport; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000378:metabolism; D020195:Epilepsy, Reflex / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics* / Q000502:physiology; D008297:Male; D020125:Mutation, Missense; D000075702:Nedd4 Ubiquitin Protein Ligases; D010375:Pedigree; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D029867:Xenopus Proteins
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D015222:Sodium Channels; D029867:Xenopus Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618482:Nedd4 protein, Xenopus; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases