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Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures

Nature Genetics volume 28, pages 49–52 (2001)Cite this article

Abstract

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants1,2. We have found a mutation in a gene encoding a GABAA receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the γ2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

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Figure 1: Pedigree of a four-generation family with CAE and FS.
Figure 2: Position of the c.245G→A mutation in GABRG2.
Figure 3: Electrophysiological analyses of GABRG2 and the mutant protein in Xenopus laevis oocytes.

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References

  1. Hauser, W.A., Annegers, J.F. & Kurland, L.T. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34, 453–468 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399 (1989).

  3. Steinlein, O.K. et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet. 11, 201–203 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Biervert, C. et al. A potassium channel mutation in neonatal human epilepsy. Science 279, 403–406 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Charlier, C. et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet. 18, 53–55 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Singh, N.A. et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nature Genet. 18, 25–29 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Wallace, R.H. et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel β1 subunit gene SCN1B. Nature Genet. 19, 366–370 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Escayg, A. et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 24, 343–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. De Fusco, M. et al. The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genet. 26, 275–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Scheffer, I.E. & Berkovic, S.F. Genetics of the epilepsies. Curr. Opin. Pediatr. 12, 536–542 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Snead, O.C., Depaulis, A., Vergnes, M. & Marescaux, C. Absence epilepsy: advances in experimental animal models. Adv. Neurol. 79, 253–278 (1999).

    PubMed  Google Scholar 

  12. Sander, T. et al. Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor α 1 and γ 2 subunit gene cluster on chromosome 5. Epilepsy Res. 23, 235–244 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Sander, T. et al. Linkage analysis between idiopathic generalized epilepsies and the GABA(A) receptor α5 and β3 and γ3 subunit gene cluster on chromosome 15. Acta Neurol. Scand. 96, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Sander, T. et al. Association analysis of exonic variants of the gene encoding the GABAB receptor and idiopathic generalized epilepsy. Am. J. Med. Genet. 88, 305–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Fong, G.C. et al. Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3–4-Hz spike and multispike-slow wave complexes: linkage to chromosome 8q24. Am. J. Hum. Genet. 63, 1117–1129 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Feucht, M. et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3. Biol. Psychiatry 46, 997–1002 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Italian League Against Epilepsy Genetic Collaborative Group. Concordance of clinical forms of epilepsy in families with several affected members. Epilepsia 34, 819–826 (1993).

  18. Kucken, A.M., Wagner, D.A., Ward, P.R., Boileau, J.A. & Czajkowski, C. Identification of benzodiazepine binding site residues in the γ2 subunit of the γ-aminobutyric acid(A) receptor. Mol. Pharmacol. 57, 932–939 (2000).

    CAS  PubMed  Google Scholar 

  19. Draguhn, A., Verdorn, T.A., Ewert, M., Seeburg, P.H. & Sakmann, B. Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron 5, 781–788 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Knudsen, F.U. Febrile seizures: treatment and prognosis. Epilepsia 41, 2–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Olsen, R.W. & Avoli, M. GABA and epileptogenesis. Epilepsia 38, 399–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Steriade, M., McCormick, D.A. & Sejnowski, T.J. Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Brooks-Kayal, A.R. & Pritchett, D.B. Developmental changes in human γ-aminobutyric acid A receptor subunit composition. Ann. Neurol. 34, 687–693 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Scheffer, I.E. & Berkovic, S.F. Generalized epilepsy with febrile seizures plus—a genetic disorder with heterogeneous clinical phenotypes. Brain 120, 479–490 (1997).

    Article  PubMed  Google Scholar 

  25. Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cottingham, R.W., Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  27. Schaffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank B. Cromer for discussions and the family for participation. Supported by the National Health & Medical Research Council, Australian Research Council, Women's & Children's Hospital Foundation, National Heart Foundation, Bionomics Limited and a University of Melbourne Scholarship (to C.M.).

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Authors and Affiliations

  1. Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide, South Australia, Australia

    Robyn H. Wallace, Louise A. Harkin, Grant R. Sutherland & John C. Mulley

  2. Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia

    Robyn H. Wallace, Louise A. Harkin & Grant R. Sutherland

  3. Department of Genetics, University of Adelaide, Adelaide, South Australia, Australia

    Grant R. Sutherland & John C. Mulley

  4. Epilepsy Research Institute and Department of Medicine (Neurology), University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, Victoria, Australia

    Carla Marini, Ingrid E. Scheffer & Samuel F. Berkovic

  5. Department of Physiology, University of Melbourne, Parkville, Victoria, Australia

    Steven Petrou, David N. Bowser, Rekha G. Panchal & David A. Williams

  6. Department of Neurology, Royal Children's Hospital, Victoria, Australia

    Ingrid E. Scheffer & Samuel F. Berkovic

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  1. Robyn H. Wallace
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  2. Carla Marini
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Correspondence to Robyn H. Wallace.

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Wallace, R., Marini, C., Petrou, S. et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 28, 49–52 (2001). https://doi.org/10.1038/ng0501-49

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