[en] 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.
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).
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).
Hauser, W.A. & Kurland, L.T. The epidemiology of epilepsy in Rochester, Minnesota. 1935 through 1967. Epilepsia 16, 1-66 (1975).
Leppert, M. et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337, 647-648 (1989).
Ryan, S.G. et al. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann. Neurol. 29, 469-473 (1991).
Malafosse, A. et al. Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20. Hum. Genet. 89, 54-58 (1992).
Steinlein, O., Fischer, C., Keil, R., Smigrodzki, R. & Vogel, F. D20S19, linked to low-voltage EEG, 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).
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).
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).
Leppert, M. et al. Searching for human epilepsy genes: a progress report. Brain Pathol. 3, 357-369 (1993).
Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet 12, 17-23 (1996).
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).
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).
Kozak, M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. J. Mol. Biol. 196, 947-950 (1987).
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).
Wei, A., Jegla, T. & Salkoff, L. Eight potassium channel families revealed by the C. elegans genome project. Neuropharmacology 35, 805-829 (1996).
Keating, M.T. & Sanguinetti, M.C. Pathophysiology of ion channel mutations. Curr. Opin. Genet. Dev. 6, 326-333 (1996).
Meldrum, B.S. Neurotransmission in epilepsy. Epilepsia 36, S30-S35 (1995).
McNamara, J.O. Cellular and molecular basis of epilepsy. J. Neurosci. 14, 3413-3425 (1994).
Sanguinetti, M.C. et al. Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 384, 80-83 (1996).
Patil, N. et al. A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet. 11, 126-129 (1995).
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).
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).
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).
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).
Chandy, K.G. & Gutman, G.A., Handbook of Receptors and Channels: Ligand and Voltage-Gated Ion Channels 1-71 (CRC, Ann Arbor, Michigan, 1995).
Jan, L.Y. & Jan, Y.N. Cloned potassium channels from eukaryotes and prokaryotes. Annu. Rev. Neurosci. 20, 91-123 (1997).
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).
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).
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).
Heginbotham, L., Lu, Z., Abramson, T. & MacKinnon, R. Mutations in the K+ channel signature sequence. Biophys. J. 66, 1061-1067 (1994).
Hidalgo, P. & MacKinnon, R. Revealing the architecture of a K+ channel pore through murant cycles with a peptide inhibitor. Science 268, 307-310 (1995).
Guipponi, M. et al. Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q. Hum. Mol. Genet. 6, 473-477 (1997).
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).
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).
