GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy
Article first published online: 2 JAN 2014
© 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 Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Annals of Neurology
Volume 75, Issue 1, pages 147–154, January 2014
How to Cite
Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hörtnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S. and Weckhuysen, S. (2014), GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Ann Neurol., 75: 147–154. doi: 10.1002/ana.24073
- Issue published online: 12 FEB 2014
- Article first published online: 2 JAN 2014
- Accepted manuscript online: 23 NOV 2013 01:28AM EST
- Manuscript Accepted: 18 NOV 2013
- Manuscript Revised: 10 NOV 2013
- Manuscript Received: 19 AUG 2013
To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations.
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.
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.
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