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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, Geider K, Laube B, Schwake M, Finsterwalder K, Franke A, Schilhabel M, Jähn JA, Muhle H, Boor R, Van Paesschen W, Caraballo R, Fejerman N, Weckhuysen S, De Jonghe P, Larsen J, Møller RS, Hjalgrim H, Addis L, Tang S, Hughes E, Pal DK, Veri K, Vaher U, Talvik T, Dimova P, Guerrero López R, Serratosa JM, Linnankivi T, Lehesjoki AE, Ruf S, Wolff M, Buerki S, Wohlrab G, Kroell J, Datta AN, Fiedler B, Kurlemann G, Kluger G, Hahn A, Haberlandt DE, Kutzer C, Sperner J, Becker F, Weber YG, Feucht M, Steinböck H, Neophythou B, Ronen GM, Gruber-Sedlmayr U, Geldner J, Harvey RJ, Hoffmann P, Herms S, Altmüller J, Toliat MR, Thiele H, Nürnberg P, Wilhelm C, Stephani U, Helbig I, Lerche H, Zimprich F, Neubauer BA, Biskup S, von Spiczak S.
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Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
Figure 1: Structural and functional consequences of the missense mutation in GRIN2A encoding p.Ala243Val. Functional analysis of the missense alteration p.Ala243Val (index subject 1) showed a significant reduction in high-affinity Zn2+ inhibition, whereas current amplitude, glutamate and glycine affinities and relative open-state probability remained unchanged. (a) Topology model of an NR1 and an NR2A subunit. The position of p.Ala243Val is indicated by a star in the NR2A subunit consisting of an N-terminal domain (NTD), the ligand-binding domain (LBD) including the S1 and S2 peptide segments, three transmembrane segments (M1–M3), a re-entrant pore loop (P) and an intracellular C-terminal domain (CTD). Ala243 lies within the Zn2+-binding NTD in NR2A. (b) Model of the NR2A NTD (cyan) together with an adjacent NR1 NTD (green). An enlarged view shows Ala243 within the Zn2+-binding NR2A NTD. (c) Pharmacological characterization of the apparent agonist affinities of wild-type and mutant NMDA receptors. Glutamate dose-response curves of wild-type NR1-NR2A (black triangles) and mutant NR1–NR2A Ala243Val (red squares) NMDA receptors were measured upon heterologous expression in Xenopus laevis oocytes by two-electrode voltage clamping (TEVC; n = 5). Similar glutamate and glycine (data not shown) concentrations were required for a half-maximal response (EC50); representative dose-response curves are shown for wild-type and mutant receptors. I/Imax is the relative current, normalized to the maximal inducible current (in μA). (d) Maximal current responses and kinetics of the open-channel blocker MK-801 for wild-type and mutant NMDA receptors show similar channel activity. The maximal agonist-inducible currents and rate kinetics of MK-801–mediated inhibition were used to determine the relative open-state probability (Po) of wild-type NR1-NR2A compared to mutant NR1–NR2A Ala243Val NMDA receptors. Data are shown as mean + s.d. (e) Inhibition of agonist-evoked currents by low concentrations of Zn2+ at wild-type and mutant NMDA receptors. Currents for NR1-NR2A, NR1-NR2A–NR2A Ala243Val and NR1–NR2A Ala243Val receptors show a gradual loss of high-affinity inhibition by 0.1 μM Zn2+ (n = 5; P < 0.01, Student's t test). Traces show currents for the NMDA receptors in the absence (black) and presence (red) of 0.1 μM Zn2+.
Figure 2: Pedigrees of affected individuals with available family information. Analysis of possible segregation of the respective mutation in family members could be performed for index subject 2 and for 19 of 27 mutation carriers in cohorts II and III where DNA samples were available from family members. The respective GRIN2A mutation segregated with a variable phenotype of seizures, pathologic EEG patterns and/or intellectual disability in family members. A few individuals carried the familial mutation but did not present any clinical features, indicating incomplete penetrance of the mutations or mosaicism. However, subclinical phenotypes (for example, EEG patterns) have not been investigated in these individuals. Pedigree 87-4 suggests phenocopy in the proband's brother. WT, wild type.
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