Neuroscience Bulletin

, Volume 33, Issue 4, pp 455–477 | Cite as

Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy

  • Feng Wei
  • Li-Min Yan
  • Tao Su
  • Na He
  • Zhi-Jian Lin
  • Jie Wang
  • Yi-Wu Shi
  • Yong-Hong Yi
  • Wei-Ping Liao


Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.


Epilepsy Ion channel gene Epilepsy gene Genetics Gene function Pathogenic mechanism 



Research work from our laboratory cited in this review was supported by the National Natural Science Foundation of China (81571273, 81571274, 81501124, 81271434, and 81301107), Omics-based precision medicine of epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China (2016YFC0904400), the Natural Science Foundation of Guangdong Province, China (2014A030313489), Science and Technology Planning Projects of Guangdong Province, China (2012B031800404 and 2013B051000084), the Department of Education of Guangdong Province, China (2013CXZDA022, 2013KJCX0156, and 2012KJCX009), the Foundation for High-level Talents in Higher Education of Guangdong Province, China (2013-167), Yangcheng Scholar Research Projects of Guangzhou Municipal College (12A016S and 12A017G), and Science and Technology Projects of Guangzhou, Guangdong Province, China (2014J4100069, 201508020011, 201604020161, and 201607010002).


  1. 1.
    Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003, 349: 1257–1266.PubMedCrossRefGoogle Scholar
  2. 2.
    Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, et al. Epilepsy-associated genes. Seizure 2017, 44: 11–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Kohling R, Wolfart J. Potassium channels in epilepsy. Cold Spring Harb Perspect Med 2016, 6, Pii: a022871. Google Scholar
  4. 4.
    Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995, 11: 201–203.PubMedCrossRefGoogle Scholar
  5. 5.
    Weiland S, Witzemann V, Villarroel A, Propping P, Steinlein O. An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Lett 1996, 398: 91–96.PubMedCrossRefGoogle Scholar
  6. 6.
    Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K, et al. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology 1999, 53: 1749–1753.PubMedCrossRefGoogle Scholar
  7. 7.
    Steinlein OK, Hoda JC, Bertrand S, Bertrand D. Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. Seizure 2012, 21: 118–123.PubMedCrossRefGoogle Scholar
  8. 8.
    Meng H, Xu HQ, Yu L, Lin GW, He N, Su T, et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat 2015, 36: 573–580.PubMedCrossRefGoogle Scholar
  9. 9.
    Liao WP, Shi YW, Long YS, Zeng Y, Li T, Yu MJ, et al. Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: associated with loss of function of Na(v) 1.1. Epilepsia 2010, 51: 1669–1678.PubMedCrossRefGoogle Scholar
  10. 10.
    Hartshorne RP, Catterall WA. Purification of the saxitoxin receptor of the sodium channel from rat brain. Proc Natl Acad Sci U S A 1981, 78: 4620–4624.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kruger LC, O’Malley HA, Hull JM, Kleeman A, Patino GA, Isom LL. beta1-C121W is down but not out: epilepsy-associated Scn1b-C121W results in a deleterious gain-of-function. J Neurosci 2016, 36: 6213–6224.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Namadurai S, Yereddi NR, Cusdin FS, Huang CL, Chirgadze DY, Jackson AP. A new look at sodium channel beta subunits. Open Biol 2015, 5: 140192.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Trimmer JS, Rhodes KJ. Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol 2004, 66: 477–519.PubMedCrossRefGoogle Scholar
  14. 14.
    Spruston N. Assembling cell ensembles. Cell 2014, 157: 1502–1504.PubMedCrossRefGoogle Scholar
  15. 15.
    Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes GH. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 2011, 76: 594–600.PubMedCrossRefGoogle Scholar
  16. 16.
    Li N, Zhang J, Guo JF, Yan XX, Xia K, Tang BS. Novel mutation of SCN1A in familial generalized epilepsy with febrile seizures plus. Neurosci Lett 2010, 480: 211–214.PubMedCrossRefGoogle Scholar
  17. 17.
    Volkers L, Kahlig KM, Verbeek NE, Das JH, van Kempen MJ, Stroink H, et al. Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome. Eur J Neurosci 2011, 34: 1268–1275.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Brackenbury WJ, Isom LL. Na channel beta subunits: overachievers of the ion channel family. Front Pharmacol 2011, 2: 53.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Thomas EA, Xu R, Petrou S. Computational analysis of the R85C and R85H epilepsy mutations in Na+ channel beta1 subunits. Neuroscience 2007, 147: 1034–1046.PubMedCrossRefGoogle Scholar
  20. 20.
    Wallace RH, Wang DW, Singh R, Scheffer IE, George AL, Jr., Phillips HA, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998, 19: 366–370.PubMedCrossRefGoogle Scholar
  21. 21.
    Ogiwara I, Nakayama T, Yamagata T, Ohtani H, Mazaki E, Tsuchiya S, et al. A homozygous mutation of voltage-gated sodium channel beta(I) gene SCN1B in a patient with Dravet syndrome. Epilepsia 2012, 53: e200–203.PubMedCrossRefGoogle Scholar
  22. 22.
    Patino GA, Claes LR, Lopez-Santiago LF, Slat EA, Dondeti RS, Chen C, et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci 2009, 29: 10764–10778.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, et al. Clinical spectrum of SCN2A mutations. Brain Dev 2012, 34: 541–545.PubMedCrossRefGoogle Scholar
  24. 24.
    Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 2010, 588: 1841–1848.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Misra SN, Kahlig KM, George AL, Jr. Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia 2008, 49: 1535–1545.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010, 133: 1403–1414.PubMedCrossRefGoogle Scholar
  27. 27.
    Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci 2004, 24: 2690–2698.PubMedCrossRefGoogle Scholar
  28. 28.
    Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology 2009, 73: 1046–1053.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Planells-Cases R, Caprini M, Zhang J, Rockenstein EM, Rivera RR, Murre C, et al. Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice. Biophys J 2000, 78: 2878–2891.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Xu R, Thomas EA, Jenkins M, Gazina EV, Chiu C, Heron SE, et al. A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel. Mol Cell Neurosci 2007, 35: 292–301.PubMedCrossRefGoogle Scholar
  31. 31.
    Beckh S, Noda M, Lubbert H, Numa S. Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development. EMBO J 1989, 8: 3611–3616.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010, 51: 1650–1658.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Holland KD, Kearney JA, Glauser TA, Buck G, Keddache M, Blankston JR, et al. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett 2008, 433: 65–70.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Vanoye CG, Gurnett CA, Holland KD, George AL, Jr., Kearney JA. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 2014, 62: 313–322.PubMedCrossRefGoogle Scholar
  35. 35.
    Chen YJ, Shi YW, Xu HQ, Chen ML, Gao MM, Sun WW, et al. Electrophysiological differences between the same pore region mutation in SCN1A and SCN3A. Mol Neurobiol 2015, 51: 1263–1270.PubMedCrossRefGoogle Scholar
  36. 36.
    Wagnon JL, Barker BS, Hounshell JA, Haaxma CA, Shealy A, Moss T, et al. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Ann Clin Transl Neurol 2016, 3: 114–123.PubMedCrossRefGoogle Scholar
  37. 37.
    Veeramah KR, O’Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 2012, 90: 502–510.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Estacion M, O’Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD, et al. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis 2014, 69: 117–123.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    de Kovel CG, Meisler MH, Brilstra EH, van Berkestijn FM, van ‘t Slot R, van Lieshout S, et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res 2014, 108: 1511–1518.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Blanchard MG, Willemsen MH, Walker JB, Dib-Hajj SD, Waxman SG, Jongmans MC, et al. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet 2015, 52: 330–337.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet 2007, 16: 2892–2899.PubMedCrossRefGoogle Scholar
  42. 42.
    Blumenfeld H, Lampert A, Klein JP, Mission J, Chen MC, Rivera M, et al. Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis. Epilepsia 2009, 50: 44–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Peiffer A, Thompson J, Charlier C, Otterud B, Varvil T, Pappas C, et al. A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. Ann Neurol 1999, 46: 671–678.PubMedCrossRefGoogle Scholar
  44. 44.
    Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G, Drenth JP, et al. Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7. Mol Pain 2011, 7: 92.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Singh NA, Pappas C, Dahle EJ, Claes LR, Pruess TH, De Jonghe P, et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet 2009, 5: e1000649.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Anderson PA, Greenberg RM. Phylogeny of ion channels: clues to structure and function. Comp Biochem Physiol B Biochem Mol Biol 2001, 129: 17–28.PubMedCrossRefGoogle Scholar
  47. 47.
    Syrbe S, Hedrich UB, Riesch E, Djemie T, Muller S, Moller RS, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 2015, 47: 393–399.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Pena SD, Coimbra RL. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet 2015, 87: e1–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Brew HM, Gittelman JX, Silverstein RS, Hanks TD, Demas VP, Robinson LC, et al. Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol 2007, 98: 1501–1525.PubMedCrossRefGoogle Scholar
  50. 50.
    Liu PW, Bean BP. Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons. J Neurosci 2014, 34: 4991–5002.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Torkamani A, Bersell K, Jorge BS, Bjork RL, Friedman JR, Bloss CS, et al. De novo KCNB1 mutations in epileptic encephalopathy. Annals of Neurology 2014, 76: 529–540.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Saitsu H, Akita T, Tohyama J, Goldberg-Stern H, Kobayashi Y, Cohen R, et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci Rep 2015, 5: 15199.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Thiffault I, Speca DJ, Austin DC, Cobb MM, Eum KS, Safina NP, et al. A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. J Gen Physiol 2015, 146: 399–410.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 2015, 47: 39–46.PubMedCrossRefGoogle Scholar
  55. 55.
    Rudy B, McBain CJ. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci 2001, 24: 517–526.PubMedCrossRefGoogle Scholar
  56. 56.
    Jerng HH, Pfaffinger PJ, Covarrubias M. Molecular physiology and modulation of somatodendritic A-type potassium channels. Mol Cell Neurosci 2004, 27: 343–369.PubMedCrossRefGoogle Scholar
  57. 57.
    Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet 2014, 23: 3481–3489.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, et al. A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis 2006, 24: 245–253.PubMedCrossRefGoogle Scholar
  59. 59.
    Smets K, Duarri A, Deconinck T, Ceulemans B, van de Warrenburg BP, Zuchner S, et al. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy. BMC Med Genet 2015, 16: 51.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Villa C, Combi R. Potassium channels and human epileptic phenotypes: An updated overview. Front Cell Neurosci 2016, 10: 81.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Keller DI, Grenier J, Christe G, Dubouloz F, Osswald S, Brink M, et al. Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures. Can J Cardiol 2009, 25: 455–462.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Zamorano-Leon JJ, Yanez R, Jaime G, Rodriguez-Sierra P, Calatrava-Ledrado L, Alvarez-Granada RR, et al. KCNH2 gene mutation: a potential link between epilepsy and long QT-2 syndrome. J Neurogenet 2012, 26: 382–386.PubMedCrossRefGoogle Scholar
  63. 63.
    Partemi S, Cestele S, Pezzella M, Campuzano O, Paravidino R, Pascali VL, et al. Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death. Epilepsia 2013, 54: e112–116.PubMedCrossRefGoogle Scholar
  64. 64.
    Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 2013, 54: 1270–1281.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Yang Y, Vasylyev DV, Dib-Hajj F, Veeramah KR, Hammer MF, Dib-Hajj SD, et al. Multistate structural modeling and voltage-clamp analysis of epilepsy/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state. J Neurosci 2013, 33: 16586–16593.PubMedCrossRefGoogle Scholar
  66. 66.
    Brown DA, Passmore GM. Neural KCNQ (Kv7) channels. Br J Pharmacol 2009, 156: 1185–1195.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Wuttke TV, Penzien J, Fauler M, Seebohm G, Lehmann-Horn F, Lerche H, et al. Neutralization of a negative charge in the S1-S2 region of the KV7.2 (KCNQ2) channel affects voltage-dependent activation in neonatal epilepsy. J Physiol 2008, 586: 545–555.PubMedCrossRefGoogle Scholar
  68. 68.
    Hunter J, Maljevic S, Shankar A, Siegel A, Weissman B, Holt P, et al. Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy. Neurobiol Dis 2006, 24: 194–201.PubMedCrossRefGoogle Scholar
  69. 69.
    Soldovieri MV, Cilio MR, Miceli F, Bellini G, Miraglia del Giudice E, Castaldo P, et al. Atypical gating of M-type potassium channels conferred by mutations in uncharged residues in the S4 region of KCNQ2 causing benign familial neonatal convulsions. J Neurosci 2007, 27: 4919–4928.PubMedCrossRefGoogle Scholar
  70. 70.
    Soldovieri MV, Boutry-Kryza N, Milh M, Doummar D, Heron B, Bourel E, et al. Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum Mutat 2014, 35: 356–367.PubMedCrossRefGoogle Scholar
  71. 71.
    Ambrosino P, Alaimo A, Bartollino S, Manocchio L, De Maria M, Mosca I, et al. Epilepsy-causing mutations in Kv7.2 C-terminus affect binding and functional modulation by calmodulin. Biochim Biophys Acta 2015, 1852: 1856–1866.PubMedCrossRefGoogle Scholar
  72. 72.
    Volkers L, Rook MB, Das JH, Verbeek NE, Groenewegen WA, van Kempen MJ, et al. Functional analysis of novel KCNQ2 mutations found in patients with Benign Familial Neonatal Convulsions. Neurosci Lett 2009, 462: 24–29.PubMedCrossRefGoogle Scholar
  73. 73.
    Miceli F, Vargas E, Bezanilla F, Taglialatela M. Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain. Biophys J 2012, 102: 1372–1382.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Maljevic S, Naros G, Yalcin O, Blazevic D, Loeffler H, Caglayan H, et al. Temperature and pharmacological rescue of a folding-defective, dominant-negative KV 7.2 mutation associated with neonatal seizures. Hum Mutat 2011, 32: E2283–2293.PubMedCrossRefGoogle Scholar
  75. 75.
    Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 2003, 126: 2726–2737.PubMedCrossRefGoogle Scholar
  76. 76.
    Castaldo P, del Giudice EM, Coppola G, Pascotto A, Annunziato L, Taglialatela M. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J Neurosci 2002, 22: Rc199.Google Scholar
  77. 77.
    Maljevic S, Wuttke TV, Lerche H. Nervous system KV7 disorders: breakdown of a subthreshold brake. J Physiol 2008, 586: 1791–1801.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Schroeder BC, Kubisch C, Stein V, Jentsch TJ. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 1998, 396: 687–690.PubMedCrossRefGoogle Scholar
  79. 79.
    Richards MC, Heron SE, Spendlove HE, Scheffer IE, Grinton B, Berkovic SF, et al. Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet 2004, 41: e35.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Abidi A, Devaux JJ, Molinari F, Alcaraz G, Michon FX, Sutera-Sardo J, et al. A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels. Neurobiol Dis 2015, 80: 80–92.PubMedCrossRefGoogle Scholar
  81. 81.
    Orhan G, Bock M, Schepers D, Ilina EI, Reichel SN, Loffler H, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 2014, 75: 382–394.PubMedCrossRefGoogle Scholar
  82. 82.
    Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LR, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012, 71: 15–25.PubMedCrossRefGoogle Scholar
  83. 83.
    Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013, 45: 825–830.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, et al. Gene mutation analysis in 253 chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One 2015, 10: e0141782.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Miceli F, Striano P, Soldovieri MV, Fontana A, Nardello R, Robbiano A, et al. A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. Epilepsia 2015, 56: e15–20.PubMedCrossRefGoogle Scholar
  86. 86.
    Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, et al. Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 2015, 35: 3782–3793.PubMedCrossRefGoogle Scholar
  87. 87.
    Peters HC, Hu H, Pongs O, Storm JF, Isbrandt D. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat Neurosci 2005, 8: 51–60.PubMedCrossRefGoogle Scholar
  88. 88.
    Jentsch TJ. Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci 2000, 1: 21–30.PubMedCrossRefGoogle Scholar
  89. 89.
    Miceli F, Soldovieri MV, Ambrosino P, Barrese V, Migliore M, Cilio MR, et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 2013, 110: 4386–4391.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Sugiura Y, Nakatsu F, Hiroyasu K, Ishii A, Hirose S, Okada M, et al. Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC). Epilepsy Res 2009, 84: 82–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Bassi MT, Balottin U, Panzeri C, Piccinelli P, Castaldo P, Barrese V, et al. Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). Neurogenetics 2005, 6: 185–193.PubMedCrossRefGoogle Scholar
  92. 92.
    Neubauer BA, Waldegger S, Heinzinger J, Hahn A, Kurlemann G, Fiedler B, et al. KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes. Neurology 2008, 71: 177–183.PubMedCrossRefGoogle Scholar
  93. 93.
    Czirjak G, Toth ZE, Enyedi P. Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes. J Neurophysiol 2007, 98: 1213–1222.PubMedCrossRefGoogle Scholar
  94. 94.
    Jorge BS, Campbell CM, Miller AR, Rutter ED, Gurnett CA, Vanoye CG, et al. Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility. Proc Natl Acad Sci U S A 2011, 108: 5443–5448.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gu N, Vervaeke K, Storm JF. BK potassium channels facilitate high-frequency firing and cause early spike frequency adaptation in rat CA1 hippocampal pyramidal cells. J Physiol 2007, 580: 859–882.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 2005, 37: 733–738.PubMedCrossRefGoogle Scholar
  97. 97.
    Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012, 44: 1188–1190.PubMedCrossRefGoogle Scholar
  98. 98.
    Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O’Malley K, et al. Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci 2009, 12: 745–750.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012, 44: 1255–1259.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Kim GE, Kronengold J, Barcia G, Quraishi IH, Martin HC, Blair E, et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep 2014, 9: 1661–1672.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Ishii A, Shioda M, Okumura A, Kidokoro H, Sakauchi M, Shimada S, et al. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 2013, 531: 467–471.PubMedCrossRefGoogle Scholar
  102. 102.
    Allen NM, Conroy J, Shahwan A, Lynch B, Correa RG, Pena SD, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia 2016, 57: e12–17.PubMedCrossRefGoogle Scholar
  103. 103.
    Rizzo F, Ambrosino P, Guacci A, Chetta M, Marchese G, Rocco T, et al. Characterization of two de novoKCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci 2016, 72: 54–63.PubMedCrossRefGoogle Scholar
  104. 104.
    Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol 2015, 78: 995–999.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014, 75: 581–590.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Rajakulendran S, Hanna MG. The role of calcium channels in epilepsy. Cold Spring Harb Perspect Med 2016, 6: a022723.PubMedCrossRefGoogle Scholar
  107. 107.
    Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 2011, 145: 1036–1048.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Epi KCEaekce, Epi KC. De Novo Mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 2016, 99: 287–298.Google Scholar
  109. 109.
    Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, et al. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. Journal of Biological Chemistry 2004, 279: 9681–9684.PubMedCrossRefGoogle Scholar
  110. 110.
    Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003, 54: 239–243.PubMedCrossRefGoogle Scholar
  111. 111.
    Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 2005, 25: 4844–4855.PubMedCrossRefGoogle Scholar
  112. 112.
    Heron SE, Khosravani H, Varela D, Bladen C, Williams TC, Newman MR, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 2007, 62: 560–568.PubMedCrossRefGoogle Scholar
  113. 113.
    Edvardson S, Oz S, Abulhijaa FA, Taher FB, Shaag A, Zenvirt S, et al. Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. J Med Genet 2013, 50: 118–123.PubMedCrossRefGoogle Scholar
  114. 114.
    Brill J, Klocke R, Paul D, Boison D, Gouder N, Klugbauer N, et al. entla, a novel epileptic and ataxic Cacna2d2 mutant of the mouse. J Biol Chem 2004, 279: 7322–7330.PubMedCrossRefGoogle Scholar
  115. 115.
    Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 2000, 66: 1531–1539.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Burgess DL, Jones JM, Meisler MH, Noebels JL. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 1997, 88: 385–392.PubMedCrossRefGoogle Scholar
  117. 117.
    Ronjat M, Kiyonaka S, Barbado M, De Waard M, Mori Y. Nuclear life of the voltage-gated Cacnb4 subunit and its role in gene transcription regulation. Channels (Austin) 2013, 7: 119–125.CrossRefGoogle Scholar
  118. 118.
    Stolting G, Fischer M, Fahlke C. CLC channel function and dysfunction in health and disease. Front Physiol 2014, 5: 378.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Saint-Martin C, Gauvain G, Teodorescu G, Gourfinkel-An I, Fedirko E, Weber YG, et al. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Human Mutation 2009, 30: 397–405.PubMedCrossRefGoogle Scholar
  120. 120.
    Haug K, Warnstedt M, Alekov AK, Sander T, Ramirez A, Poser B, et al. Retraction: Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 2009, 41: 1043.Google Scholar
  121. 121.
    Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 2007, 27: 6581–6589.PubMedCrossRefGoogle Scholar
  122. 122.
    Palmer EE, Stuhlmann T, Weinert S, Haan E, Van Esch H, Holvoet M, et al. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females. Mol Psychiatry 2016, doi: 10.1038/mp.2016.135.PubMedGoogle Scholar
  123. 123.
    Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer AP, et al. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Molecular Psychiatry 2016, 21: 133–148.PubMedCrossRefGoogle Scholar
  124. 124.
    Hur J, Jeong HJ, Park J, Jeon S. Chloride channel 4 is required for nerve growth factor-induced TrkA signaling and neurite outgrowth in PC12 cells and cortical neurons. Neuroscience 2013, 253: 389–397.PubMedCrossRefGoogle Scholar
  125. 125.
    Baumann SW, Baur R, Sigel E. Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement. J Biol Chem 2002, 277: 46020–46025.PubMedCrossRefGoogle Scholar
  126. 126.
    Shen D, Hernandez CC, Shen W, Hu N, Poduri A, Shiedley B, et al. De novo GABRG2 mutations associated with epileptic encephalopathies. Brain 2016. doi: 10.1093/brain/aww272.Google Scholar
  127. 127.
    Hirose S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 2014, 213: 55–85.PubMedCrossRefGoogle Scholar
  128. 128.
    Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002, 31: 184–189.PubMedCrossRefGoogle Scholar
  129. 129.
    Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 2006, 59: 983–987.PubMedCrossRefGoogle Scholar
  130. 130.
    Johannesen K, Marini C, Pfeffer S, Moller RS, Dorn T, Niturad C, et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology 2016, 87: 1140–1151.PubMedCrossRefGoogle Scholar
  131. 131.
    Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De novo mutations in epileptic encephalopathies. Nature 2013, 501: 217–221.PubMedCrossRefGoogle Scholar
  132. 132.
    Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Moller RS, Hjalgrim H, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 2014, 82: 1245–1253.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Kodera H, Ohba C, Kato M, Maeda T, Araki K, Tajima D, et al. De novo GABRA1 mutations in Ohtahara and West syndromes. Epilepsia 2016, 57: 566–573.PubMedCrossRefGoogle Scholar
  134. 134.
    Lachance-Touchette P, Brown P, Meloche C, Kinirons P, Lapointe L, Lacasse H, et al. Novel alpha1 and gamma2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci 2011, 34: 237–249.PubMedCrossRefGoogle Scholar
  135. 135.
    Arain FM, Boyd KL, Gallagher MJ. Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor alpha1 subunit. Epilepsia 2012, 53: e161–165.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Dibbens LM, Harkin LA, Richards M, Hodgson BL, Clarke AL, Petrou S, et al. The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies. Neurosci Lett 2009, 453: 162–165.PubMedCrossRefGoogle Scholar
  137. 137.
    Hernandez CC, Gurba KN, Hu N, Macdonald RL. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6beta22 and 6beta2 GABA(A) receptor channel gating and expression. J Physiol 2011, 589: 5857–5878.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Fillman SG, Duncan CE, Webster MJ, Elashoff M, Weickert CS. Developmental co-regulation of the beta and gamma GABAA receptor subunits with distinct alpha subunits in the human dorsolateral prefrontal cortex. Int J Dev Neurosci 2010, 28: 513–519.PubMedCrossRefGoogle Scholar
  139. 139.
    Janve VS, Hernandez CC, Verdier KM, Hu N, Macdonald RL. Epileptic encephalopathy de novo GABRB mutations impair GABAA receptor function. Ann Neurol 2016. doi: 10.1002/ana.24631.Google Scholar
  140. 140.
    Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, Watkins JC, et al. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet 2016. doi: 10.1136/jmedgenet-2016-104083.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet 2008, 82: 1249–1261.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Audenaert D, Schwartz E, Claeys KG, Claes L, Deprez L, Suls A, et al. A novel GABRG2 mutation associated with febrile seizures. Neurology 2006, 67: 687–690.PubMedCrossRefGoogle Scholar
  143. 143.
    Johnston AJ, Kang JQ, Shen W, Pickrell WO, Cushion TD, Davies JS, et al. A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes. Neurobiol Dis 2014, 64: 131–141.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Reinthaler EM, Dejanovic B, Lal D, Semtner M, Merkler Y, Reinhold A, et al. Rare variants in gamma-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Ann Neurol 2015, 77: 972–986.PubMedCrossRefGoogle Scholar
  145. 145.
    Tian M, Macdonald RL. The intronic GABRG2 mutation, IVS6+2T->G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated gamma2 subunit. J Neurosci 2012, 32: 5937–5952.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Wang J, Shen D, Xia G, Shen W, Macdonald RL, Xu D, et al. Differential protein structural disturbances and suppression of assembly partners produced by nonsense GABRG2 epilepsy mutations: implications for disease phenotypic heterogeneity. Sci Rep 2016, 6: 35294.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme JF, et al. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 2001, 28: 46–48.PubMedGoogle Scholar
  148. 148.
    Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH, et al. Truncation of the GABA(A)-Receptor γ2 Subunit in a Family with Generalized Epilepsy with Febrile Seizures Plus. Am J Hum Genet 2002, 70: 530–536.PubMedCrossRefGoogle Scholar
  149. 149.
    Hirose S. A new paradigm of channelopathy in epilepsy syndromes: intracellular trafficking abnormality of channel molecules. Epilepsy Res 2006, 70 Suppl 1: S206–217.PubMedCrossRefGoogle Scholar
  150. 150.
    Huang X, Hernandez CC, Hu N, Macdonald RL. Three epilepsy-associated GABRG2 missense mutations at the gamma+/beta− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. Neurobiol Dis 2014, 68: 167–179.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Sun H, Zhang Y, Liang J, Liu X, Ma X, Wu H, et al. SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. J Hum Genet 2008, 53: 769–774.PubMedCrossRefGoogle Scholar
  152. 152.
    Kang JQ, Macdonald RL. Molecular pathogenic basis for GABRG2 mutations associated with a spectrum of epilepsy syndromes, from generalized absence epilepsy to dravet syndrome. JAMA Neurol 2016, 73: 1009–1016.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Reid CA, Kim T, Phillips AM, Low J, Berkovic SF, Luscher B, et al. Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology 2013, 80: 1003–1008.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Kang JQ, Shen W, Zhou C, Xu D, Macdonald RL. The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. Nat Neurosci 2015, 18: 988–996.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Carver CM, Reddy DS. Neurosteroid structure-activity relationships for functional activation of extrasynaptic deltaGABA(A) receptors. J Pharmacol Exp Ther 2016, 357: 188–204.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, et al. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 2004, 13: 1315–1319.PubMedCrossRefGoogle Scholar
  157. 157.
    Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001, 11: 327–335.PubMedCrossRefGoogle Scholar
  158. 158.
    Lemke JR, Geider K, Helbig KL, Heyne HO, Schutz H, Hentschel J, et al. Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology 2016, 86: 2171–2178.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 2011, 88: 306–316.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994, 12: 529–540.PubMedCrossRefGoogle Scholar
  161. 161.
    Suryavanshi PS, Ugale RR, Yilmazer-Hanke D, Stairs DJ, Dravid SM. GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice. Br J Pharmacol 2014, 171: 799–809.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013, 45: 1067–1072.PubMedCrossRefGoogle Scholar
  163. 163.
    Conroy J, McGettigan PA, McCreary D, Shah N, Collins K, Parry-Fielder B, et al. Towards the identification of a genetic basis for Landau-Kleffner syndrome. Epilepsia 2014, 55: 858–865.PubMedCrossRefGoogle Scholar
  164. 164.
    Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013, 45: 1061–1066.PubMedCrossRefGoogle Scholar
  165. 165.
    Carvill GL, Regan BM, Yendle SC, O’Roak BJ, Lozovaya N, Bruneau N, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013, 45: 1073–1076.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010, 42: 1021–1026.PubMedCrossRefGoogle Scholar
  167. 167.
    Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, et al. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun 2014, 5: 3251.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Hildebrand MS, Myers CT, Carvill GL, Regan BM, Damiano JA, Mullen SA, et al. A targeted resequencing gene panel for focal epilepsy. Neurology 2016, 86: 1605–1612.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Lemke JR, Hendrickx R, Geider K, Laube B, Schwake M, Harvey RJ, et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol 2014, 75: 147–154.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, et al. GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Am J Hum Genet 2016, 99: 802–816.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Son CD, Moss FJ, Cohen BN, Lester HA. Nicotine normalizes intracellular subunit stoichiometry of nicotinic receptors carrying mutations linked to autosomal dominant nocturnal frontal lobe epilepsy. Mol Pharmacol 2009, 75: 1137–1148.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Leniger T, Kananura C, Hufnagel A, Bertrand S, Bertrand D, Steinlein OK. A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy. Epilepsia 2003, 44: 981–985.PubMedCrossRefGoogle Scholar
  173. 173.
    Chen Z, Wang L, Wang C, Chen Q, Zhai Q, Guo Y, et al. Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy. Int J Clin Exp Med 2015, 8: 9063–9070.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Rozycka A, Steinborn B, Trzeciak WH. The 1674+11C>T polymorphism of CHRNA4 is associated with juvenile myoclonic epilepsy. Seizure 2009, 18: 601–603.PubMedCrossRefGoogle Scholar
  175. 175.
    Aridon P, Marini C, Di Resta C, Brilli E, De Fusco M, Politi F, et al. Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet 2006, 79: 342–350.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Conti V, Aracri P, Chiti L, Brusco S, Mari F, Marini C, et al. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology 2015, 84: 1520–1528.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Trivisano M, Terracciano A, Milano T, Cappelletti S, Pietrafusa N, Bertini ES, et al. Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy. Epilepsia 2015, 56: e53–57.PubMedCrossRefGoogle Scholar
  178. 178.
    Ballesteros-Yanez I, Benavides-Piccione R, Bourgeois JP, Changeux JP, DeFelipe J. Alterations of cortical pyramidal neurons in mice lacking high-affinity nicotinic receptors. Proc Natl Acad Sci U S A 2010, 107: 11567–11572.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Gullo F, Manfredi I, Lecchi M, Casari G, Wanke E, Becchetti A. Multi-electrode array study of neuronal cultures expressing nicotinic beta2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy. Front Neural Circuits 2014, 8: 87.Google Scholar
  180. 180.
    Gillentine MA, Berry LN, Goin-Kochel RP, Ali MA, Ge J, Guffey D, et al. The cognitive and behavioral phenotypes of individuals with CHRNA7 duplications. J Autism Dev Disord 2016. doi: 10.1007/s10803-016-2961-8.Google Scholar
  181. 181.
    Klaassen A, Glykys J, Maguire J, Labarca C, Mody I, Boulter J. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc Natl Acad Sci U S A 2006, 103: 19152–19157.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Aracri P, Consonni S, Morini R, Perrella M, Rodighiero S, Amadeo A, et al. Tonic modulation of GABA release by nicotinic acetylcholine receptors in layer V of the murine prefrontal cortex. Cereb Cortex 2010, 20: 1539–1555.PubMedCrossRefGoogle Scholar
  183. 183.
    DiFrancesco JC, DiFrancesco D. Dysfunctional HCN ion channels in neurological diseases. Front Cell Neurosci 2015, 6: 174.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Nava C, Dalle C, Rastetter A, Striano P, de Kovel CG, Nabbout R, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 2014, 46: 640–645.PubMedCrossRefGoogle Scholar
  185. 185.
    Huang Z, Walker MC, Shah MM. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J Neurosci 2009, 29: 10979–10988.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Nakamura Y, Shi X, Numata T, Mori Y, Inoue R, Lossin C, et al. Novel HCN2 mutation contributes to febrile seizures by shifting the channel’s kinetics in a temperature-dependent manner. PLoS One 2013, 8: e80376.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    DiFrancesco JC, Barbuti A, Milanesi R, Coco S, Bucchi A, Bottelli G, et al. Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy. J Neurosci 2011, 31: 17327–17337.PubMedCrossRefGoogle Scholar
  188. 188.
    Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, et al. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A 2001, 98: 6384–6389.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 2010, 75: 1454–1458.PubMedCrossRefGoogle Scholar
  190. 190.
    Wang J, Li Y, Hui Z, Cao M, Shi R, Zhang W, et al. Functional analysis of potassium channels in Kv7.2 G271V mutant causing early onset familial epilepsy. Brain Res 2015, 1616: 112–122.PubMedCrossRefGoogle Scholar
  191. 191.
    Dedek K, Fusco L, Teloy N, Steinlein OK. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res 2003, 54: 21–27.PubMedCrossRefGoogle Scholar
  192. 192.
    Miceli F, Soldovieri MV, Lugli L, Bellini G, Ambrosino P, Migliore M, et al. Neutralization of a unique, negatively-charged residue in the voltage sensor of K V 7.2 subunits in a sporadic case of benign familial neonatal seizures. Neurobiol Dis 2009, 34: 501–510.PubMedCrossRefGoogle Scholar
  193. 193.
    Lee US, Cui J. {Beta} subunit-specific modulations of BK channel function by a mutation associated with epilepsy and dyskinesia. J Physiol 2009, 587: 1481–1498.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet 2014, 23: 3200–3211.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Tang B, Sander T, Craven KB, Hempelmann A, Escayg A. Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy. Neurobiol Dis 2008, 29: 59–70.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore 2017

Authors and Affiliations

  • Feng Wei
    • 1
    • 2
  • Li-Min Yan
    • 1
  • Tao Su
    • 1
  • Na He
    • 1
  • Zhi-Jian Lin
    • 1
  • Jie Wang
    • 1
  • Yi-Wu Shi
    • 1
  • Yong-Hong Yi
    • 1
  • Wei-Ping Liao
    • 1
  1. 1.Institute of Neuroscience, Department of Neurology of The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of ChinaGuangzhou Medical UniversityGuangzhouChina
  2. 2.Department of NeurologyGuangdong Second Provincial General HospitalGuangzhouChina

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