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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Abstract

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)1,2. 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.

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Figure 1: Structural and functional consequences of the missense mutation in GRIN2A encoding p.Ala243Val.
Figure 2: Pedigrees of affected individuals with available family information.

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References

  1. Berg, A.T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51, 676–685 (2010).

    Article  Google Scholar 

  2. Gobbi, G., Boni, A. & Filippini, M. The spectrum of idiopathic Rolandic epilepsy syndromes and idiopathic occipital epilepsies: from the benign to the disabling. Epilepsia 47 (suppl. 2), 62–66 (2006).

    Article  Google Scholar 

  3. Stephani, U. Typical semiology of benign childhood epilepsy with centrotemporal spikes (BCECTS). Epileptic Disord. 2 (suppl. 1), S3–S4 (2000).

    PubMed  Google Scholar 

  4. Hughes, J.R. A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy Behav. 20, 247–253 (2011).

    Article  Google Scholar 

  5. Bali, B. et al. Autosomal dominant inheritance of centrotemporal sharp waves in rolandic epilepsy families. Epilepsia 48, 2266–2272 (2007).

    PubMed  PubMed Central  Google Scholar 

  6. Vadlamudi, L. et al. Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration. Epilepsia 47, 550–555 (2006).

    Article  Google Scholar 

  7. Neubauer, B.A. et al. Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14. Neurology 51, 1608–1612 (1998).

    Article  CAS  Google Scholar 

  8. Pal, D.K., Li, W., Clarke, T., Lieberman, P. & Strug, L.J. Pleiotropic effects of the 11p13 locus on developmental verbal dyspraxia and EEG centrotemporal sharp waves. Genes Brain Behav. 9, 1004–1012 (2010).

    Article  CAS  Google Scholar 

  9. Strug, L.J. et al. Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4). Eur. J. Hum. Genet. 17, 1171–1181 (2009).

    Article  CAS  Google Scholar 

  10. Reutlinger, C. et al. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. Epilepsia 51, 1870–1873 (2010).

    Article  CAS  Google Scholar 

  11. Lemke, J.R. et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53, 1387–1398 (2012).

    Article  CAS  Google Scholar 

  12. Helbig, I. et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41, 160–162 (2009).

    Article  CAS  Google Scholar 

  13. Claes, L.R. et al. The SCN1A variant database: a novel research and diagnostic tool. Hum. Mutat. 30, E904–E920 (2009).

    Article  Google Scholar 

  14. Marini, C. et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia 48, 1678–1685 (2007).

    Article  CAS  Google Scholar 

  15. Paoletti, P. Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 33, 1351–1365 (2011).

    Article  Google Scholar 

  16. Di Maio, R., Mastroberardino, P.G., Hu, X., Montero, L.M. & Greenamyre, J.T. Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: implications for epileptogenesis. Neurobiol. Dis. 49C, 87–98 (2012).

    Google Scholar 

  17. Frasca, A. et al. Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity. Neurobiol. Dis. 43, 507–515 (2011).

    Article  CAS  Google Scholar 

  18. Niimura, M. et al. Changes in phosphorylation of the NMDA receptor in the rat hippocampus induced by status epilepticus. J. Neurochem. 92, 1377–1385 (2005).

    Article  CAS  Google Scholar 

  19. Lacey, C.J., Bryant, A., Brill, J. & Huguenard, J.R. Enhanced NMDA receptor–dependent thalamic excitation and network oscillations in stargazer mice. J. Neurosci. 32, 11067–11081 (2012).

    Article  CAS  Google Scholar 

  20. Lesca, G. et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 53, 1526–1538 (2012).

    Article  CAS  Google Scholar 

  21. Endele, S. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat. Genet. 42, 1021–1026 (2010).

    Article  CAS  Google Scholar 

  22. Balu, D.T. & Coyle, J.T. Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction. Brain Res. 1392, 1–7 (2011).

    Article  CAS  Google Scholar 

  23. Marini, C. et al. The genetics of Dravet syndrome. Epilepsia 52 (suppl. 2), 24–29 (2011).

    Article  CAS  Google Scholar 

  24. Henson, M.A. et al. Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS ONE 7, e42327 (2012).

    Article  CAS  Google Scholar 

  25. Ghasemi, M. & Schachter, S.C. The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy Behav. 22, 617–640 (2011).

    Article  Google Scholar 

  26. Engel, J. Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 42, 796–803 (2001).

    Article  Google Scholar 

  27. Fernández, I.S. et al. The tower of Babel: survey on concepts and terminology in electrical status epilepticus in sleep and continuous spikes and waves during sleep in North America. Epilepsia 54, 741–750 (2013).

    Article  Google Scholar 

  28. Schmermund, A. et al. Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle. Am. Heart J. 144, 212–218 (2002).

    Article  Google Scholar 

  29. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  Google Scholar 

  30. Weckx, S. et al. novoSNP, a novel computational tool for sequence variation discovery. Genome Res. 15, 436–442 (2005).

    Article  CAS  Google Scholar 

  31. Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).

    Article  CAS  Google Scholar 

  32. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all subjects and family members for their participation in this study. Furthermore, we are grateful to all clinicians referring patients and probands for genetic research. We would like to thank all lab technicians for technical assistance with mutation and CNV analysis.

The authors would like to thank the National Heart, Lung and Blood Institute (NHLBI) GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

S.v.S. received institutional support from Christian-Albrechts University Kiel and a scholarship from the German Epilepsy Society for research activities (Otfrid-Foerster-Stipendium). J.R.L. (32EP30_136042/1), P.D.J. (G.A.136.11.N and FWO/ESF-ECRP), T.T. (SF0180035s08), J.M.S. (EUI-EURC-2011-4325) and I.H. (HE5415/3-1) received financial support within the EuroEPINOMICS-RES network, and A.-E.L. (Academy of Finland, grant 141549), P.N. (Nu50/8-1), H.L. (Le1030/11-1), F.Z. (FWF I643-B09) and B.A.N. (Ne416/5-1) received financial support within the EuroEPINOMICS-CoGIE network within the Eurocores framework of the European Science Foundation (ESF). H.L. and S. Biskup received further support from the German Federal Ministry for Education and Research (BMBF; H.L.: NGFNplus/EMINet 01GS08123; H.L. and S. Biskup, IonNeurONet 01GM1105A). M. Schwake received financial support from the German Research Foundation (DFG; SFB877). J.M.S. received support from the Spanish Government (grant SAF2010-18586). D.K.P. and L.A. received support from a European Union Marie Curie International Reintegration Award of the Seventh Framework Programme (PIRG05-GA-2009-248866) and from the Waterloo Foundation, the Ali Paris Fund for Landau-Kleffner Syndrome Research and Education, the Charles Sykes Epilepsy Research Trust and the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service (NHS) Foundation Trust.

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Contributions

Study design: J.R.L., S.v.S., I.H., S. Biskup, E.M.R., F.Z., D.L., B.A.N. and H.L. Subject ascertainment and phenotyping: I.H., J.A.J., H.M., U.S., R.B., W.v.P., R.C., N.F., M.A., S.W., P.D.J., J.L., R.S.M., H.H., L.A., S.T., E.H., D.K.P., K.V., U.V., T.T., P.D., R.G.L., J.M.S., T.L., A.-E.L., S. Buerki, G.W., J.K., A.N.D., S.R., M.W., B.F., G. Kurlemann, G. Kluger, A.H., D.E.H., C.K., J.S., F.B., Y.G.W., H.L., M.F., H.S., B.N., G.M.R., U.G.-S., J.G., F.Z., B.A.N., J.R.L. and S.v.S. Mutation analysis of cohort I: S.v.S., I.H., K.F., M. Schilhabel and A.F. Next-generation sequencing panel analysis of index subjects: I.S. and S. Biskup Mutation analysis of cohort II: C.W., J.R.L. and S. Biskup Segregation analysis of cohort II: C.W. and S. Biskup Mutation analysis of cohort III: E.M.R., D.L., J.A., M.R.T., H.T. and P.N. Segregation analysis of cohort III: E.M.R. and D.L. CNV control cohort: P.H. and S.H. Statistical analysis: M.N. Functional analysis of GRIN2A missense mutation: M. Schwake, K.G. and B.L. Data interpretation: H.L., R.J.H., M. Schwake, B.L., J.R.L., I.H., S.v.S., S. Biskup, D.L., E.M.R., M.N., B.A.N. and F.Z. Manuscript writing: J.R.L., S.v.S., S. Biskup, B.L., M.N., E.M.R., F.Z., D.L. and B.A.N. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Holger Lerche or Sarah von Spiczak.

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The authors declare no competing financial interests.

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Lemke, J., Lal, D., Reinthaler, E. et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 45, 1067–1072 (2013). https://doi.org/10.1038/ng.2728

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