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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Nature Genetics volume 45, pages 10671072 (2013) | Download Citation

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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References

  1. 1.

    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).

  2. 2.

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

  3. 3.

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

  4. 4.

    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).

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

    , , , & Pleiotropic effects of the 11p13 locus on developmental verbal dyspraxia and EEG centrotemporal sharp waves. Genes Brain Behav. 9, 1004–1012 (2010).

  9. 9.

    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).

  10. 10.

    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).

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

    , , , & 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).

  17. 17.

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

  18. 18.

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

  19. 19.

    , , & Enhanced NMDA receptor–dependent thalamic excitation and network oscillations in stargazer mice. J. Neurosci. 32, 11067–11081 (2012).

  20. 20.

    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).

  21. 21.

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

  22. 22.

    & 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).

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

    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).

  27. 27.

    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).

  28. 28.

    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).

  29. 29.

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

  30. 30.

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

  31. 31.

    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).

  32. 32.

    , , & Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81, 3443–3446 (1984).

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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.

Author information

Author notes

    • Johannes R Lemke
    • , Dennis Lal
    •  & Eva M Reinthaler

    These authors contributed equally to this work.

    • Fritz Zimprich
    • , Bernd A Neubauer
    • , Saskia Biskup
    •  & Sarah von Spiczak

    These authors jointly directed this work.

Affiliations

  1. Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.

    • Johannes R Lemke
  2. Partners of EuroEPINOMICS.

    • Johannes R Lemke
    • , Dennis Lal
    • , Eva M Reinthaler
    • , Johanna A Jähn
    • , Hiltrud Muhle
    • , Sarah Weckhuysen
    • , Peter De Jonghe
    • , Jan Larsen
    • , Rikke S Møller
    • , Helle Hjalgrim
    • , Deb K Pal
    • , Kadi Veri
    • , Ulvi Vaher
    • , Tiina Talvik
    • , Rosa Guerrero López
    • , José M Serratosa
    • , Tarja Linnankivi
    • , Anna-Elina Lehesjoki
    • , Andreas Hahn
    • , Felicitas Becker
    • , Yvonne G Weber
    • , Janine Altmüller
    • , Mohammad R Toliat
    • , Holger Thiele
    • , Peter Nürnberg
    • , Ulrich Stephani
    • , Ingo Helbig
    • , Holger Lerche
    • , Fritz Zimprich
    • , Bernd A Neubauer
    •  & Sarah von Spiczak
  3. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.

    • Dennis Lal
    • , Michael Nothnagel
    • , Janine Altmüller
    • , Mohammad R Toliat
    • , Holger Thiele
    •  & Peter Nürnberg
  4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Dennis Lal
    •  & Peter Nürnberg
  5. Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.

    • Dennis Lal
    • , Andreas Hahn
    •  & Bernd A Neubauer
  6. Department of Neurology, Medical University of Vienna, Vienna, Austria.

    • Eva M Reinthaler
    •  & Fritz Zimprich
  7. CeGaT, GmbH, Tübingen, Germany.

    • Isabelle Steiner
    • , Christian Wilhelm
    •  & Saskia Biskup
  8. Department of Neuropediatrics, University of Tübingen, Tübingen, Germany.

    • Michael Alber
    • , Susanne Ruf
    •  & Markus Wolff
  9. Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Germany.

    • Kirsten Geider
    •  & Bodo Laube
  10. Department of Chemistry, Biochemistry III, Bielefeld University, Bielefeld, Germany.

    • Michael Schwake
  11. Department of Neuropediatrics, University Medical Center Schleswig-Holstein and Christian-Albrecht University Kiel, Kiel, Germany.

    • Katrin Finsterwalder
    • , Johanna A Jähn
    • , Hiltrud Muhle
    • , Rainer Boor
    • , Ulrich Stephani
    • , Ingo Helbig
    •  & Sarah von Spiczak
  12. Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany.

    • Andre Franke
    •  & Markus Schilhabel
  13. Northern German Epilepsy Center for Children and Adolescents, Schwentinental, Germany.

    • Rainer Boor
    •  & Ulrich Stephani
  14. Department of Neurology, University Hospital, Leuven, Belgium.

    • Wim Van Paesschen
  15. Department of Neurology, Juan P. Garrahan Pediatric Hospital, Buenos Aires, Argentina.

    • Roberto Caraballo
    •  & Natalio Fejerman
  16. Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.

    • Sarah Weckhuysen
    •  & Peter De Jonghe
  17. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

    • Sarah Weckhuysen
    •  & Peter De Jonghe
  18. Epilepsy Center Kempenhaeghe, Hans Berger Clinic, Oosterhout, The Netherlands.

    • Sarah Weckhuysen
  19. Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.

    • Peter De Jonghe
  20. Danish Epilepsy Center, Dianalund, Denmark.

    • Jan Larsen
    • , Rikke S Møller
    •  & Helle Hjalgrim
  21. Department of Clinical Neuroscience, Institute of Psychiatry, King's College Hospital, King's College London, London, UK.

    • Laura Addis
    • , Shan Tang
    •  & Deb K Pal
  22. Department of Paediatric Neuroscience, Clinical Neurology, King's College London, London, UK.

    • Elaine Hughes
  23. Department of Pediatrics, Children's Clinic of Tartu University Hospital, University of Tartu, Tartu, Estonia.

    • Kadi Veri
    • , Ulvi Vaher
    •  & Tiina Talvik
  24. Clinic of Child Neurology, St. Naum University Hospital of Neurology and Psychiatry, Sofia, Bulgaria.

    • Petia Dimova
  25. Department of Neurology, Instituta de Investigaciones Sanitarias (IIS) Fundación Jiménez Díaz University Hospital and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain.

    • Rosa Guerrero López
    •  & José M Serratosa
  26. Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Tarja Linnankivi
  27. Neuroscience Center, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland.

    • Anna-Elina Lehesjoki
  28. Department of Neuropediatrics, University Children's Hospital Inselspital, Bern, Switzerland.

    • Sarah Buerki
  29. Neuropediatric and Neurophysiologic Department, University Children's Hospital, Zurich, Switzerland.

    • Gabriele Wohlrab
  30. Swiss Epilepsy Center, Zurich, Switzerland.

    • Judith Kroell
  31. Department of Neuropediatrics, University Children's Hospital, Basel, Switzerland.

    • Alexandre N Datta
  32. Department of Neuropediatrics, University Children's Hospital, University Medical Center Münster, Münster, Germany.

    • Barbara Fiedler
    •  & Gerhard Kurlemann
  33. Department of Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen Clinic Vogtareuth, Vogtareuth, Germany.

    • Gerhard Kluger
  34. Department of Neuropediatrics, University Children's Hospital, Innsbruck, Austria.

    • D Edda Haberlandt
  35. Kinderzentrum St. Martin, Regensburg, Germany.

    • Christina Kutzer
  36. Neuropediatric Medical Practice, Lübeck, Germany.

    • Jürgen Sperner
  37. Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.

    • Felicitas Becker
    • , Yvonne G Weber
    •  & Holger Lerche
  38. Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

    • Martha Feucht
  39. Pediatric Medical Practice, Vienna, Austria.

    • Hannelore Steinböck
  40. Department of Pediatrics, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.

    • Birgit Neophythou
  41. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

    • Gabriel M Ronen
  42. Department of Pediatrics, Medical University of Graz, Graz, Austria.

    • Ursula Gruber-Sedlmayr
  43. Department of Pediatrics, Hospital Socio-Medical Center (SMZ) Süd Kaiser Franz Josef Spital, Vienna, Austria.

    • Julia Geldner
  44. Department of Pharmacology, University College London (UCL) School of Pharmacy, London, UK.

    • Robert J Harvey
  45. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Per Hoffmann
    •  & Stefan Herms
  46. Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Per Hoffmann
    •  & Stefan Herms
  47. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  48. Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.

    • Saskia Biskup
  49. German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.

    • Saskia Biskup

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Holger Lerche or Sarah von Spiczak.

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https://doi.org/10.1038/ng.2728

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