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

L. M. Dibbens, J. Ekberg, I. Taylor, B. L. Hodgson, Sarah Jane Conroy, I. L. Lensink, Sharad Kumar, M. A. Zielinski, L. A. Harkin, G. R. Sutherland, David J. Adams, S. F. Berkovic, I. E. Scheffer, J. C. Mulley, Philip Poronnik

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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 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 v1.2 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.

Original languageEnglish
Pages (from-to)750-755
Number of pages6
JournalGenes, Brain and Behavior
Volume6
Issue number8
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

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Reflex Epilepsy
Voltage-Gated Sodium Channels
Ion Channels
Down-Regulation
Genes
Generalized Epilepsy
Ubiquitin-Protein Ligases
Xenopus
Oocytes
Epilepsy
Seizures
Proteins
Mutation
Idiopathic Generalized Epilepsy

Cite this

Dibbens, L. M., Ekberg, J., Taylor, I., Hodgson, B. L., Conroy, S. J., Lensink, I. L., ... Poronnik, P. (2007). NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes, Brain and Behavior, 6(8), 750-755. https://doi.org/10.1111/j.1601-183X.2007.00305.x
Dibbens, L. M. ; Ekberg, J. ; Taylor, I. ; Hodgson, B. L. ; Conroy, Sarah Jane ; Lensink, I. L. ; Kumar, Sharad ; Zielinski, M. A. ; Harkin, L. A. ; Sutherland, G. R. ; Adams, David J. ; Berkovic, S. F. ; Scheffer, I. E. ; Mulley, J. C. ; Poronnik, Philip. / NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. In: Genes, Brain and Behavior. 2007 ; Vol. 6, No. 8. pp. 750-755.
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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 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 v1.2 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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Dibbens, LM, Ekberg, J, Taylor, I, Hodgson, BL, Conroy, SJ, Lensink, IL, Kumar, S, Zielinski, MA, Harkin, LA, Sutherland, GR, Adams, DJ, Berkovic, SF, Scheffer, IE, Mulley, JC & Poronnik, P 2007, 'NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity' Genes, Brain and Behavior, vol. 6, no. 8, pp. 750-755. https://doi.org/10.1111/j.1601-183X.2007.00305.x

NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. / Dibbens, L. M.; Ekberg, J.; Taylor, I.; Hodgson, B. L.; Conroy, Sarah Jane; Lensink, I. L.; Kumar, Sharad; Zielinski, M. A.; Harkin, L. A.; Sutherland, G. R.; Adams, David J.; Berkovic, S. F.; Scheffer, I. E.; Mulley, J. C.; Poronnik, Philip.

In: Genes, Brain and Behavior, Vol. 6, No. 8, 11.2007, p. 750-755.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity

AU - Dibbens, L. M.

AU - Ekberg, J.

AU - Taylor, I.

AU - Hodgson, B. L.

AU - Conroy, Sarah Jane

AU - Lensink, I. L.

AU - Kumar, Sharad

AU - Zielinski, M. A.

AU - Harkin, L. A.

AU - Sutherland, G. R.

AU - Adams, David J.

AU - Berkovic, S. F.

AU - Scheffer, I. E.

AU - Mulley, J. C.

AU - Poronnik, Philip

PY - 2007/11

Y1 - 2007/11

N2 - 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 v1.2 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.

AB - 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 v1.2 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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