Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns

Nature Genetics volume 18, pages 25–29 (1998)Cite this article

Abstract

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Ronen, G.M., Rosales, T.O., Connolly, M., Anderson, V.E. & Leppert, M. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 43, 1355–1360 (1993).

    Article  CAS  Google Scholar 

  2. Plouin, P. Benign infantile neonatal convulsions in Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects (eds Malafosse, A. et al.) 39–44 (John Libbey, London, 1994).

  3. Mauser, W.A. & Kurland, L.T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16, 1–66 (1975).

    Article  Google Scholar 

  4. Leppert, M. et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337, 647–648 (1989).

    Article  CAS  Google Scholar 

  5. Ryan, S.G. et al. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann. Neurol. 29, 469–473 (1991).

    Article  CAS  Google Scholar 

  6. Malafosse, A. et al. Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20. Hum. Genet. 89, 54–58 (1992).

    Article  CAS  Google Scholar 

  7. Steinlein, O., Fischer, C, Keil, R., Smigrodzki, R. & Vogel, F. D20S19, linked to low-voltage EEC, benign neonatal convulsions, and Fanconi anaemia, maps to a region of enhanced recombination and is localized between CpG islands. Hum. Mol. Genet. 1, 325–329 (1992).

    Article  CAS  Google Scholar 

  8. Lewis, T.B., Leach, R.J., Ward, K., O'Connell, P. & Ryan, S.G. Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q. Am. J. Hum. Genet. 53, 670–675 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Steinlein, O., Schuster, V., Fischer, C. & Haussler, M. Benign familial neonatal convulsions: confirmation of genetic heterogeneity and further evidence for a second locus on chromosome 8q. Hum. Genet. 95, 411–415 (1995).

    Article  CAS  Google Scholar 

  10. Leppert, M. et al. Searching for human epilepsy genes: a progress report. Brain Pathol. 3, 357–369 (1993).

    Article  CAS  Google Scholar 

  11. Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet 12, 17–23 (1996).

    Article  Google Scholar 

  12. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  13. Neyroud, N. et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet. 15, 186–189 (1997).

    Article  CAS  Google Scholar 

  14. Kozak, M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. J. Mol. Biol. 196, 947–950 (1987).

    Article  CAS  Google Scholar 

  15. Yokoyama, M., Nishi, Y., Yoshii, J., Okubo, K. & Matsubara, K. Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles. DNA Res. 3, 311–320 (1996).

    Article  CAS  Google Scholar 

  16. Wei, A., Jegla, T. & Salkoff, L. Eight potassium channel families revealed by the C elegans genome project. Neuropharmacology 35, 805–829 (1996).

    Article  CAS  Google Scholar 

  17. Keating, M.T. & Sanguinetti, M.C. Pathophysiology of ion channel mutations. Curr. Opin. Genet Dev. 6, 326–333 (1996).

    Article  CAS  Google Scholar 

  18. Meldrum, B.S. Neurotransmission in epilepsy. Epilepsia 36, S30–S35 (1995).

    Article  Google Scholar 

  19. McNamara, J.O. Cellular and molecular basis of epilepsy. J. Neurosci. 14, 3413–3425 (1994).

    Article  CAS  Google Scholar 

  20. Sanguinetti, M.C. et al. Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac lKs potassium channel. Nature 384, 80–83 (1996).

    Article  CAS  Google Scholar 

  21. Patil, N. et al. A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet. 11, 126–129 (1995).

    Article  CAS  Google Scholar 

  22. Signorini, S., Liao, Y.J., Duncan, S.A., Jan, L.Y. & Stoffel, M. Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. Proc. Natl. Acad. Sci. USA 94, 923–927 (1997).

    Article  CAS  Google Scholar 

  23. Russell, M.W., Dick, M. II, Collins, F.S. & Brody, L.C. KVLQT1 mutations in three families with familial or sporadic long QT syndrome. Hum. Mol. Genet 5, 1319–1324 (1996).

    Article  CAS  Google Scholar 

  24. Yang, W.-P. et al. KVLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proc Natl. Acad. Sci. USA 94, 4017–4021 (1997).

    Article  CAS  Google Scholar 

  25. Browne, D.L. et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genet. 8, 136–140(1994).

    Article  CAS  Google Scholar 

  26. Chandy, K.G. & Gutman, G.A. Handbook of Receptors and Channels: Ligand and Voltage-Gated Ion Channels 1–71 (CRC, Ann Arbor, Michigan, 1995).

  27. Jan, L.Y. & Jan, Y.N. Cloned potassium channels from eukaryotes and prokaryotes. Annu. Rev. Neurosci. 20, 91–123 (1997).

    Article  CAS  Google Scholar 

  28. Lopez, G.A., Jan, Y.N. & Jan, L.Y. Evidence that the S6 segment of the Shaker voltage-gated K+ channel comprises part of the pore. Nature 367, 179–182 (1994).

    Article  CAS  Google Scholar 

  29. Tytgat, J. Mutations in the P-region of a mammalian potassium channel (RCK1): a comparison with the Shaker potassium channel. Biochem. Biophys. Res. Commun. 203, 513–518 (1994).

    Article  CAS  Google Scholar 

  30. Nakamura, R.L., Anderson, J.A. & Gaber, R.F. Determination of key structural requirements of a K+ channel pore. J. Biol. Chem. 272, 1011–1118 (1997).

    Article  CAS  Google Scholar 

  31. L, Lu, Z., Abramson, T.& MacKinnon, R. Mutations in the K+ channel signature sequence.Biophys. J. 66, 1061–1067 (1994).

  32. Hidalgo, P. & MacKinnon, R. Revealing the architecture of a K+ channel pore through murant cycles with a peptide inhibitor. Science 268, 307–310 (1995).

    Article  CAS  Google Scholar 

  33. Guipponi, M. et al. Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q. Hum. Mol. Genet 6, 473–477 (1997).

    Article  CAS  Google Scholar 

  34. Vigevano, F. et al. Benign infantile familial convulsions in Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects (eds Malafosse, A. et al.) 45–49 (John Libbey, London, 1994).

  35. Ptacek, L.J. Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul. Disord. 7, 250–255 (1997).

    Article  CAS  Google Scholar 

  36. Sanguinetti, M.C. & Spector, P.S. Potassium channelopathies. Neuropharmacology 36, 755–762 (1997).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Utah, Salt Lake City, Utah, 84112, USA

    Nanda A. Singh, Carole Charlier, Dora Stauffer, Andy Peiffer & Mark Leppert

  2. Department of Cellular & Structural Biology, University of Texas Health Sciences Center, San Antonio, Texas, 78284, USA

    Barbara R. DuPont & Robin J. Leach

  3. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, 84112, USA

    Roberta Melis

  4. Department of Pediatrics, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada

    Gabriel M. Ronen

  5. Department of Pediatrics, Malmo University Hospital, S205021, Malmö, Sweden

    Ingrid Bjerre

  6. Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, 29425, USA

    Thomas Quattlebaum

  7. The Children's Mercy Hospital, 2401 Gillham Road, Kansas City, Missouri, 64108, USA

    Jerome V. Murphy

  8. The Neurology Group, P.C., 1340DeKalb Street, Norristown, Pennsylvania, 19401, USA

    Malcolm L. McHarg

  9. Boston University School of Public Health, Boston, Massachusetts, 02118, USA

    David Gagnon

  10. Dr. C.A. Janeway Health Center, St. John's, Newfoundland, Al A 1R8, Canada

    Teodoro O. Rosales

  11. Department of Epidemiology, University of Minnesota, Minneapolis, Minnesota, 55455, USA

    V. Elving Anderson

Authors
  1. Nanda A. Singh
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Carole Charlier
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Dora Stauffer
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Barbara R. DuPont
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Robin J. Leach
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Roberta Melis
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Gabriel M. Ronen
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Ingrid Bjerre
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Thomas Quattlebaum
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Jerome V. Murphy
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Malcolm L. McHarg
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. David Gagnon
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Teodoro O. Rosales
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Andy Peiffer
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. V. Elving Anderson
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Mark Leppert
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, N., Charlier, C., Stauffer, D. et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18, 25–29 (1998). https://doi.org/10.1038/ng0198-25

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0198-25

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing