GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy

J R Lemke; R Hendrickx; K Geider; B Laube; M Schwake; Robert J Harvey; V M James; A Pepler; I Steiner; K Hörtnagel; J Neidhardt; S Ruf; M Wolff; D Bartholdi; R Caraballo; K Platzer; A Suls; P De Jonghe; S Biskup; S Weckhuysen

doi:10.1002/ana.24073

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GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy

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GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy

J R Lemke, R Hendrickx, K Geider, B Laube, M Schwake, Robert J Harvey, V M James, A Pepler, I Steiner, K Hörtnagel, …

Annals of Neurology, Vol.75(1), pp.147-154

2014

DOI: https://doi.org/10.1002/ana.24073

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Abstract

Objective To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations. Methods Using a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort. Results We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5-2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg2+ block and higher Ca2+ permeability, leading to a dramatically increased Ca2+ influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype. Interpretation We identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis. ANN NEUROL 2014;75:147-154 © 2014 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of Child Neurology Society/American Neurological Association.

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Title: GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy
Authors: J R Lemke (Author) - University Children's Hospital Inselspital, Switzerland
R Hendrickx (Author) - Vlaams Institute of Biotechnology, Belgium
K Geider (Author) - Technical University Darmstadt, Germany
B Laube (Author) - Technical University Darmstadt, Germany
M Schwake (Author) - University of Bielefeld, Germany
Robert J Harvey (Author) - University College London, United Kingdom
V M James (Author) - University College London, United Kingdom
A Pepler (Author) - University College London, United Kingdom
I Steiner (Author) - CeGaT GmbH, Germany
K Hörtnagel (Author) - CeGaT GmbH, Germany
J Neidhardt (Author) - University of Zurich, Switzerland
S Ruf (Author) - University of Tubingen, Germany
M Wolff (Author) - University of Tubingen, Germany
D Bartholdi (Author) - Klinikum Stuttgart, Germany
R Caraballo (Author) - Juan P. Garrahan Pediatric Hospital, Argentina
K Platzer (Author) - University of Lubeck, Germany
A Suls (Author)
P De Jonghe (Author) - Vlaams Institute of Biotechnology, Belgium
S Biskup (Author) - CeGaT GmbH, Germany
S Weckhuysen (Author) - Vlaams Institute of Biotechnology, Belgium
Publication details: Annals of Neurology, Vol.75(1), pp.147-154
Publisher: John Wiley & Sons Inc.
Date published: 2014
DOI: 10.1002/ana.24073
ISSN: 0364-5134
Copyright note: Copyright © 2014 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of Child Neurology Society/American Neurological Association. This is an open access article under the terms of the Creative Commons AttributionLicense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450352302621
Output Type: Journal article

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