title: GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
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 Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland; Partners of EuroEPINOMICS, RES consortium.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.forename: Rik
authors.initials: R
authors.lastname: Hendrickx
authors.forename: Kirsten
authors.initials: K
authors.lastname: Geider
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Victoria M
authors.initials: VM
authors.lastname: James
authors.forename: Alex
authors.initials: A
authors.lastname: Pepler
authors.forename: Isabelle
authors.initials: I
authors.lastname: Steiner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Susanne
authors.initials: S
authors.lastname: Ruf
authors.forename: Markus
authors.initials: M
authors.lastname: Wolff
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.forename: Roberto
authors.initials: R
authors.lastname: Caraballo
authors.forename: Konrad
authors.initials: K
authors.lastname: Platzer
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D018360:Crystallography, X-Ray; D004828:Epilepsies, Partial / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics*; D013036:Spasms, Infantile / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate