Hostname: page-component-76fb5796d-22dnz Total loading time: 0 Render date: 2024-04-26T03:53:17.429Z Has data issue: false hasContentIssue false
  • English
  • Français

The genetics and molecular biology of fever-associated seizures or epilepsy

Published online by Cambridge University Press:  17 April 2018

Hao Deng ,
Wen Zheng  and
Zhi Song
Hao Deng*
Affiliation:
Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
Wen Zheng
Affiliation:
Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China
Zhi Song
Affiliation:
Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
*
Author for Correspondence: Hao Deng, E-mail: hdeng008@yahoo.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Fever-associated seizures or epilepsy (FASE) is primarily characterised by the occurrence of a seizure or epilepsy usually accompanied by a fever. It is common in infants and children, and generally includes febrile seizures (FS), febrile seizures plus (FS+), Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFSP). The aetiology of FASE is unclear. Genetic factors may play crucial roles in FASE. Mutations in certain genes may cause a wide spectrum of phenotypical overlap ranging from isolated FS, FS+ and GEFSP to DS. Synapse-associated proteins, postsynaptic GABAA receptor, and sodium channels play important roles in synaptic transmission. Mutations in these genes may involve in the pathogenesis of FASE. Elevated temperature promotes synaptic vesicle (SV) recycling and enlarges SV size, which may enhance synaptic transmission and contribute to FASE occurring. This review provides an overview of the loci, genes, underlying pathogenesis and the fever-inducing effect of FASE. It may provide a more comprehensive understanding of pathogenesis and contribute to the clinical diagnosis of FASE.

Keywords

Epilepsyfebrile seizuresGEFSPsodium channelsynaptic transmission
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 20 , 2018 , e3
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

These authors contributed equally to this work.

References

1.Deprez, L, Jansen, A and De Jonghe, P (2009) Genetics of epilepsy syndromes starting in the first year of life. Neurology 72, 273–281Google Scholar
2.Hedera, P, et al. (2006) Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22. Epilepsia 47, 1622–1628Google Scholar
3.Tsuboi, T (1984) Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 34, 175–181CrossRefGoogle ScholarPubMed
4.Bird, TD (1987) Genetic considerations in childhood epilepsy. Epilepsia 28(suppl. 1), S71–S81Google Scholar
5.Stanhope, JM, Brody, JA and Brink, E (1972) Convulsions among the Chamorro people of Guam, Mariana Islands. I. Seizure disorders. American Journal of Epidemiology 95, 292–298Google Scholar
6.Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399Google Scholar
7.Johnson, EW, et al. (1998) Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Human Molecular Genetics 7, 63–67CrossRefGoogle Scholar
8.Nabbout, R, et al. (2002) A locus for simple pure febrile seizures maps to chromosome 6q22–q24. Brain 125, 2668–2680CrossRefGoogle ScholarPubMed
9.Poduri, A, et al. (2009) Novel susceptibility locus at chromosome 6q16.3–22.31 in a family with GEFS+. Neurology 73, 1264–1272CrossRefGoogle Scholar
10.Lagae, L, et al. (2018) Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey. Developmental Medicine & Child Neurology 60, 63–72CrossRefGoogle ScholarPubMed
11.Paul, SP, Blaikley, S and Chinthapalli, R (2012) Clinical update: febrile convulsion in childhood. Community Practitioner 85, 36–38Google Scholar
12.Baulac, S, et al. (1999) A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21–q33. American Journal of Human Genetics 65, 1078–1085CrossRefGoogle ScholarPubMed
13.Moulard, B, et al. (1999) Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24–q33. American Journal of Human Genetics 65, 1396–1400Google Scholar
14.Escayg, A, et al. (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics 24, 343–345CrossRefGoogle ScholarPubMed
15.Mantegazza, M, et al. (2005) Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proceedings of the National Academy of Sciences of the United States of America 102, 18177–18182CrossRefGoogle ScholarPubMed
16.Zuberi, SM, et al. (2011) Genotype–phenotype associations in SCN1A-related epilepsies. Neurology 76, 594–600CrossRefGoogle ScholarPubMed
17.Parihar, R and Ganesh, S (2013) The SCN1A gene variants and epileptic encephalopathies. Journal of Human Genetics 58, 573–580CrossRefGoogle ScholarPubMed
18.Orrico, A, et al. (2009) Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies. Clinical Genetics 75, 579–581CrossRefGoogle ScholarPubMed
19.Mulley, JC, et al. (2013) Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. Epilepsia 54, e122–e126Google Scholar
20.Lossin, C (2009) A catalog of SCN1A variants. Brain & Development 31, 114–130CrossRefGoogle ScholarPubMed
21.Catterall, WA (1993) Structure and function of voltage-gated ion channels. Trends in Neurosciences 16, 500–506Google Scholar
22.Isom, LL, De Jongh, KS and Catterall, WA (1994) Auxiliary subunits of voltage-gated ion channels. Neuron 12, 1183–1194Google Scholar
23.Deng, H, Xiu, X and Song, Z (2014) The molecular biology of genetic-based epilepsies. Molecular Neurobiology 49, 352–367Google Scholar
24.Meisler, MH and Kearney, JA (2005) Sodium channel mutations in epilepsy and other neurological disorders. The Journal of Clinical Investigation 115, 2010–2017Google Scholar
25.Ogiwara, I, et al. (2007) Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. The Journal of Neuroscience 27, 5903–5914Google Scholar
26.Gong, B, et al. (1999) Type I and type II Na(+) channel alpha-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain. The Journal of Comparative Neurology 412, 342–3523.0.CO;2-2>CrossRefGoogle ScholarPubMed
27.Westenbroek, RE, Merrick, DK and Catterall, WA (1989) Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 3, 695–704CrossRefGoogle ScholarPubMed
28.Duflocq, A, et al. (2008) Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Molecular and Cellular Neuroscience 39, 180–192Google Scholar
29.Lossin, C, et al. (2002) Molecular basis of an inherited epilepsy. Neuron 34, 877–884Google Scholar
30.Yu, FH, et al. (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience 9, 1142–1149CrossRefGoogle Scholar
31.Cheah, CS, et al. (2012) Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proceedings of the National Academy of Sciences of the United States of America 109, 14646–14651CrossRefGoogle Scholar
32.Martin, MS, et al. (2010) Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. The Journal of Biological Chemistry 285, 9823–9834Google Scholar
33.Han, S, et al. (2012) Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390CrossRefGoogle ScholarPubMed
34.Bouza, AA and Isom, LL (2017) Voltage-gated sodium channel β subunits and their related diseases. Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg, doi: 10.1007/164_2017_48. [Epub ahead of print]Google Scholar
35.Wallace, RH, et al. (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nature Genetics 19, 366–370CrossRefGoogle ScholarPubMed
36.Wallace, RH, et al. (2002) Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 58, 1426–1429Google Scholar
37.Steel, D, et al. (2017) Dravet syndrome and its mimics: beyond SCN1A. Epilepsia 58, 1807–1816CrossRefGoogle ScholarPubMed
38.Ogiwara, I, et al. (2012) A homozygous mutation of voltage-gated sodium channel β(I) gene SCN1B in a patient with Dravet syndrome. Epilepsia 53, e200–e203Google Scholar
39.Patino, GA, et al. (2009) A functional null mutation of SCN1B in a patient with Dravet syndrome. The Journal of Neuroscience 29, 10764–10778Google Scholar
40.Williams, CA and Battaglia, A (2013) Molecular biology of epilepsy genes. Experimental Neurology 244, 51–58Google Scholar
41.Ramadan, W, et al. (2017) Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy. Clinical Genetics 92, 327–331CrossRefGoogle ScholarPubMed
42.Reid, CA, et al. (2014) Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. Brain 137, 1701–1715Google Scholar
43.Hatch, RJ, Reid, CA and Petrou, S (2014) Enhanced in vitro CA1 network activity in a sodium channel β1(C121W) subunit model of genetic epilepsy. Epilepsia 55, 601–608Google Scholar
44.Marionneau, C, et al. (2012) The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K+ channels. The Journal of Neuroscience 32, 5716–5727Google Scholar
45.Peiffer, A, et al. (1999) A locus for febrile seizures (FEB3) maps to chromosome 2q23–24. Annals of Neurology 46, 671–678Google Scholar
46.Singh, NA, et al. (2009) A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genetics 5, e1000649CrossRefGoogle ScholarPubMed
47.Toledo-Aral, JJ, et al. (1997) Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proceedings of the National Academy of Sciences of the United States of America 94, 1527–1532Google Scholar
48.Rush, AM, et al. (2006) A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences of the United States of America 103, 8245–8250Google Scholar
49.Sage, D, et al. (2007) Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system. The Journal of Comparative Neurology 504, 363–378CrossRefGoogle ScholarPubMed
50.Ahn, HS, et al. (2011) Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Molecular Pain 7, 32CrossRefGoogle ScholarPubMed
51.Muroi, Y, et al. (2011) Selective silencing of Na(V)1.7 decreases excitability and conduction in vagal sensory neurons. The Journal of Physiology 589, 5663–5676Google Scholar
52.Holm, AN, et al. (2002) Sodium current in human jejunal circular smooth muscle cells. Gastroenterology 122, 178–187Google Scholar
53.Jo, T, et al. (2004) Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A. FEBS Letters 567, 339–343Google Scholar
54.Saleh, S, et al. (2005) Electrophysiological and molecular identification of voltage-gated sodium channels in murine vascular myocytes. The Journal of Physiology 568, 155–169Google Scholar
55.Persson, AK, et al. (2010) Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermal nerve terminals. Molecular Pain 6, 84CrossRefGoogle ScholarPubMed
56.Diss, JK, et al. (2005) A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo. Prostate Cancer and Prostatic Diseases 8, 266–273CrossRefGoogle ScholarPubMed
57.Fraser, SP, et al. (2005) Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clinical Cancer Research 11, 5381–5389Google Scholar
58.Hoffman, JF, et al. (2004) Tetrodotoxin-sensitive Na+ channels and muscarinic and purinergic receptors identified in human erythroid progenitor cells and red blood cell ghosts. Proceedings of the National Academy of Sciences of the United States of America 101, 12370–12374Google Scholar
59.Kis-Toth, K, et al. (2011) Voltage-gated sodium channel Nav1.7 maintains the membrane potential and regulates the activation and chemokine-induced migration of a monocyte-derived dendritic cell subset. Journal of Immunology 187, 1273–1280Google Scholar
60.Klugbauer, N, et al. (1995) Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. The EMBO Journal 14, 1084–1090Google Scholar
61.Rush, AM, Cummins, TR and Waxman, SG (2007) Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. The Journal of Physiology 579, 1–14CrossRefGoogle ScholarPubMed
62.Cummins, TR, Howe, JR and Waxman, SG (1998) Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. The Journal of Neuroscience 18, 9607–9619Google Scholar
63.Herzog, RI, et al. (2003) Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. The Journal of Physiology 551, 741–750Google Scholar
64.Hayes, SB and Wang, MY (2013) Na(V)1.7 pain control: a novel target. Neurosurgery 73, N16Google Scholar
65.Dib-Hajj, SD, et al. (2010) Sodium channels in normal and pathological pain. Annual Review of Neuroscience 33, 325–347Google Scholar
66.Djouhri, L, et al. (2003) Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel alpha subunit protein. The Journal of Physiology 546, 565–576Google Scholar
67.Waxman, SG, et al. (2014) Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurology 13, 1152–1160Google Scholar
68.Mansouri, M, et al. (2014) A novel nonsense mutation in SCN9A in a Moroccan child with congenital insensitivity to pain. Pediatric Neurology 51, 741–744Google Scholar
69.Weiss, J, et al. (2011) Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190Google Scholar
70.Smith, ES, et al. (2011) The molecular basis of acid insensitivity in the African naked mole-rat. Science 334, 1557–1560Google Scholar
71.Devigili, G, et al. (2014) Paroxysmal itch caused by gain-of-function Nav1.7 mutation. Pain 155, 1702–1707Google Scholar
72.Felts, PA, et al. (1997) Sodium channel alpha-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1): different expression patterns in developing rat nervous system. Brain Research. Molecular Brain Research 45, 71–82Google Scholar
73.Wallace, RH, et al. (2001) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nature Genetics 28, 49–52Google Scholar
74.Kananura, C, et al. (2002) A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Archives of Neurology 59, 1137–1141Google Scholar
75.Baulac, S, et al. (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nature Genetics 28, 46–48Google Scholar
76.Carvill, GL, et al. (2013) Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics 45, 825–830Google Scholar
77.Audenaert, D, et al. (2006) A novel GABRG2 mutation associated with febrile seizures. Neurology 67, 687–690Google Scholar
78.Harkin, LA, et al. (2002) Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. American Journal of Human Genetics 70, 530–536Google Scholar
79.Sun, H, et al. (2008) SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. Journal of Human Genetics 53, 769–774Google Scholar
80.Todd, E, et al. (2014) GABAA receptor biogenesis is impaired by the γ2 subunit febrile seizure-associated mutation, GABRG2(R177G). Neurobiology of Disease 69, 215–224CrossRefGoogle ScholarPubMed
81.Le, SV, et al. (2017) A mutation in GABRB3 associated with Dravet syndrome. American Journal of Medical Genetics. Part A 173, 2126–2131Google Scholar
82.Kang, JQ, Shen, W and Macdonald, RL (2006) Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. The Journal of Neuroscience 26, 2590–2597Google Scholar
83.Hirose, S (2014) Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Progress in Brain Research 213, 55–85CrossRefGoogle Scholar
84.Huang, X, et al. (2014) Three epilepsy-associated GABRG2 missense mutations at the γ+/β- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. Neurobiology of Disease 68, 167–179Google Scholar
85.Eugene, E, et al. (2007) GABA(A) receptor gamma 2 subunit mutations linked to human epileptic syndromes differentially affect phasic and tonic inhibition. The Journal of Neuroscience 27, 14108–14116Google Scholar
86.Bianchi, MT, et al. (2002) Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans. The Journal of Neuroscience 22, 5321–5327CrossRefGoogle ScholarPubMed
87.Hales, TG, et al. (2006) An asymmetric contribution to gamma-aminobutyric type A receptor function of a conserved lysine within TM2–3 of alpha1, beta2, and gamma2 subunits. The Journal of Biological Chemistry 281, 17034–17043Google Scholar
88.Kang, JQ, Shen, W and Macdonald, RL (2009) The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression. The Journal of Neuroscience 29, 2845–2856Google Scholar
89.Reid, CA, et al. (2013) Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology 80, 1003–1008CrossRefGoogle ScholarPubMed
90.Tan, HO, et al. (2007) Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proceedings of the National Academy of Sciences of the United States of America 104, 17536–17541Google Scholar
91.Chiu, C, et al. (2008) Developmental impact of a familial GABAA receptor epilepsy mutation. Annals of Neurology 64, 284–293Google Scholar
92.Dibbens, LM, et al. (2004) GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Human Molecular Genetics 13, 1315–1319CrossRefGoogle ScholarPubMed
93.Windpassinger, C, et al. (2002) The human gamma-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression. Gene 292, 25–31Google Scholar
94.Feng, Y, et al. (2010) Association of the GABRD gene and childhood-onset mood disorders. Genes, Brain, and Behavior 9, 668–672Google Scholar
95.Feng, HJ, et al. (2006) Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. The Journal of Neuroscience 26, 1499–1506Google Scholar
96.Macdonald, RL, Kang, JQ and Gallagher, MJ (2010) Mutations in GABAA receptor subunits associated with genetic epilepsies. The Journal of Physiology 588, 1861–1869Google Scholar
97.Moller, RS, et al. (2017) Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology 88, 483–492Google Scholar
98.Meneret, A, et al. (2012) PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 79, 170–174Google Scholar
99.Heron, SE, et al. (2012) PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. American Journal of Human Genetics 90, 152–160CrossRefGoogle ScholarPubMed
100.Zheng, W, et al. (2016) Identification of a premature termination mutation in the proline-rich transmembrane protein 2 gene in a Chinese family with febrile seizures. Molecular Neurobiology 53, 835–841Google Scholar
101.He, ZW, et al. (2014) PRRT2 mutations are related to febrile seizures in epileptic patients. International Journal of Molecular Science 15, 23408–23417Google Scholar
102.Chen, WJ, et al. (2011) Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nature Genetics 43, 1252–1255Google Scholar
103.Schubert, J, et al. (2014) Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nature Genetics 46, 1327–1332Google Scholar
104.Foletti, DL, et al. (2000) Phosphorylated syntaxin 1 is localized to discrete domains along a subset of axons. The Journal of Neuroscience 20, 4535–4544Google Scholar
105.Bragina, L, et al. (2010) Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex: analysis of synaptogyrin, vesicle-associated membrane protein, and syntaxin. Neuroscience 165, 934–943Google Scholar
106.Nakayama, J, et al. (2000) Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Human Molecular Genetics 9, 87–91Google Scholar
107.Nakayama, J, et al. (2002) A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Annals of Neurology 52, 654–657Google Scholar
108.Deprez, L, et al. (2006) Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation. Human Genetics 118, 618–625Google Scholar
109.McMillan, DR and White, PC (2010) Studies on the very large G protein-coupled receptor: from initial discovery to determining its role in sensorineural deafness in higher animals. Advances in Experimental Medicine and Biology 706, 76–86Google Scholar
110.Nikkila, H, et al. (2000) Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain. Molecular Endocrinology 14, 1351–1364Google Scholar
111.McMillan, DR, et al. (2002) Heat shock transcription factor 2 is not essential for embryonic development, fertility, or adult cognitive and psychomotor function in mice. Molecular and Cellular Biology 22, 8005–8014Google Scholar
112.McMillan, DR, et al. (2002) Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. The Journal of Biological Chemistry 277, 785–792Google Scholar
113.McMillan, DR and White, PC (2004) Loss of the transmembrane and cytoplasmic domains of the very large G-protein-coupled receptor-1 (VLGR1 or Mass1) causes audiogenic seizures in mice. Molecular and Cellular Neuroscience 26, 322–329Google Scholar
114.Scheel, H, Tomiuk, S and Hofmann, K (2002) A common protein interaction domain links two recently identified epilepsy genes. Human Molecular Genetics 11, 1757–1762CrossRefGoogle ScholarPubMed
115.Skradski, SL, et al. (2001) A novel gene causing a Mendelian audiogenic mouse epilepsy. Neuron 31, 537–544Google Scholar
116.Salzmann, A, et al. (2012) Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Human Mutation 33, 124–135Google Scholar
117.Belhedi, N, et al. (2014) Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures. Epilepsy Research 108, 144–148CrossRefGoogle ScholarPubMed
118.Wei, S, et al. (2002) Identification and characterization of three members of the human metallocarboxypeptidase gene family. The Journal of Biological Chemistry 277, 14954–14964Google Scholar
119.Hessel, EV, et al. (2014) Identification of Srp9 as a febrile seizure susceptibility gene. Annals of Clinical and Translational Neurology 1, 239–250Google Scholar
120.Siegel, V and Walter, P (1988) Functional dissection of the signal recognition particle. Trends in Biochemical Sciences 13, 314–316CrossRefGoogle ScholarPubMed
121.Lingelbach, K, et al. (1988) Isolation and characterization of a cDNA clone encoding the 19 kDa protein of signal recognition particle (SRP): expression and binding to 7SL RNA. Nucleic Acids Research 16, 9431–9442Google Scholar
122.Walter, P and Blobel, G (1983) Signal recognition particle: a ribonucleoprotein required for cotranslational translocation of proteins, isolation and properties. Methods in Enzymology 96, 682–691Google Scholar
123.Bovia, F, Bui, N and Strub, K (1994) The heterodimeric subunit SRP9/14 of the signal recognition particle functions as permuted single polypeptide chain. Nucleic Acids Research 22, 2028–2035Google Scholar
124.Lakkaraju, AK, et al. (2007) Inefficient targeting to the endoplasmic reticulum by the signal recognition particle elicits selective defects in post-ER membrane trafficking. Experimental Cell Research 313, 834–847CrossRefGoogle Scholar
125.Lakkaraju, AK, et al. (2008) SRP keeps polypeptides translocation-competent by slowing translation to match limiting ER-targeting sites. Cell 133, 440–451Google Scholar
126.Dibbens, LM, et al. (2010) Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Annals of Neurology 67, 542–546Google Scholar
127.Nakamura, Y, et al. (2013) Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner. PLoS ONE 8, e80376Google Scholar
128.Puskarjov, M, et al. (2014) A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Reports 15, 723–729Google Scholar
129.Uvarov, P, et al. (2009) Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain. The Journal of Biological Chemistry 284, 13696–13704Google Scholar
130.Khirug, S, et al. (2005) Distinct properties of functional KCC2 expression in immature mouse hippocampal neurons in culture and in acute slices. The European Journal of Neuroscience 21, 899–904Google Scholar
131.Stein, V, et al. (2004) Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride. The Journal of Comparative Neurology 468, 57–64CrossRefGoogle ScholarPubMed
132.Blaesse, P, et al. (2009) Cation-chloride cotransporters and neuronal function. Neuron 61, 820–838Google Scholar
133.Chamma, I, et al. (2012) Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission. Frontiers in Cellular Neuroscience 6, 5Google Scholar
134.Chamma, I, et al. (2013) Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons. The Journal of Neuroscience 33, 15488–15503Google Scholar
135.Li, H, et al. (2007) KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56, 1019–1033Google Scholar
136.Fiumelli, H, et al. (2013) An ion transport-independent role for the cation-chloride cotransporter KCC2 in dendritic spinogenesis in vivo. Cerebral Cortex 23, 378–388Google Scholar
137.Hekmat-Scafe, DS, et al. (2006) Mutations in the K+/Cl− cotransporter gene kazachoc (kcc) increase seizure susceptibility in Drosophila. The Journal of Neuroscience 26, 8943–8954Google Scholar
138.Woo, NS, et al. (2002) Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 12, 258–268CrossRefGoogle ScholarPubMed
139.Audenaert, D, et al. (2005) A novel susceptibility locus at 2p24 for generalised epilepsy with febrile seizures plus. Journal of Medical Genetics 42, 947–952Google Scholar
140.Nabbout, R, et al. (2007) New locus for febrile seizures with absence epilepsy on 3p and a possible modifier gene on 18p. Neurology 68, 1374–1381Google Scholar
141.Dai, XH, et al. (2008) A novel genetic locus for familial febrile seizures and epilepsy on chromosome 3q26.2–q26.33. Human Genetics 124, 423–429Google Scholar
142.Baulac, S, et al. (2008) A novel locus for generalized epilepsy with febrile seizures plus in French families. Archives of Neurology 65, 943–951Google Scholar
143.Wallace, RH, et al. (1996) Suggestion of a major gene for familial febrile convulsions mapping to 8q13–21. Journal of Medical Genetics 33, 308–312CrossRefGoogle Scholar
144.Morar, B, et al. (2011) A novel GEFS + locus on 12p13.33 in a large Roma family. Epilepsy Research 97, 198–207Google Scholar
145.Claes, L, et al. (2004) Novel locus on chromosome 12q22–q23.3 responsible for familial temporal lobe epilepsy associated with febrile seizures. Journal of Medical Genetics 41, 710–714Google Scholar
146.Gurnett, CA, et al. (2007) Additional evidence of a locus for complex febrile and afebrile seizures on chromosome 12q22–23.3. Neurogenetics 8, 61–63Google Scholar
147.Hardies, K, et al. (2013) Duplications of 17q12 can cause familial fever-related epilepsy syndromes. Neurology 81, 1434–1440Google Scholar
148.Nakayama, J, et al. (2004) Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18. Neurology 63, 1803–1807Google Scholar
149.Blair, MA, et al. (2007) Genetic variants in the IMPA2 gene do not confer increased risk of febrile seizures in Caucasian patients. European Journal of Neurology 14, 424–427Google Scholar
150.Yoshikawa, T, et al. (2000) Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2). Molecular Psychiatry 5, 165–171Google Scholar
151.Berridge, MJ and Irvine, RF (1989) Inositol phosphates and cell signalling. Nature 341, 197–205Google Scholar
152.Sjoholt, G, et al. (2000) A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients. Molecular Psychiatry 5, 172–180Google Scholar
153.Sjoholt, G, et al. (2004) Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. Molecular Psychiatry 9, 621–629Google Scholar
154.Belhedi, N, et al. (2013) A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family. BMC Genetics 14, 93Google Scholar
155.Kim, JA and Connors, BW (2012) High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus. Frontiers in Cellular Neuroscience 6, 27Google Scholar
156.Radzicki, D, et al. (2013) Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures. The Journal of Neuroscience 33, 9920–9931Google Scholar
157.Thompson, SM, Masukawa, LM and Prince, DA (1985) Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro. The Journal of Neuroscience 5, 817–824Google Scholar
158.Volgushev, M, et al. (2000) Synaptic transmission in the neocortex during reversible cooling. Neuroscience 98, 9–22Google Scholar
159.Micheva, KD and Smith, SJ (2005) Strong effects of subphysiological temperature on the function and plasticity of mammalian presynaptic terminals. The Journal of Neuroscience 25, 7481–7488Google Scholar
160.Saghazadeh, A, et al. (2014) Proinflammatory and anti-inflammatory cytokines in febrile seizures and epilepsy: systematic review and meta-analysis. Reviews in the Neurosciences 25, 281–305Google Scholar
161.Choy, M, et al. (2014) Inflammatory processes, febrile seizures, and subsequent epileptogenesis. Epilepsy Currents 14, 15–22Google Scholar
162.Heida, JG and Pittman, QJ (2005) Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 46, 1906–1913Google Scholar
163.Dube, C, et al. (2005) Interleukin-1beta contributes to the generation of experimental febrile seizures. Annals of Neurology 57, 152–155Google Scholar
164.Viviani, B, et al. (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. The Journal of Neuroscience 23, 8692–8700Google Scholar
165.Vezzani, A, et al. (1999) Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. The Journal of Neuroscience 19, 5054–5065Google Scholar
166.Vezzani, A, et al. (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proceedings of the National Academy of Sciences of the United States of America 97, 11534–11539Google Scholar
167.Virta, M, Hurme, M and Helminen, M (2002) Increased frequency of interleukin-1beta (−511) allele 2 in febrile seizures. Pediatric Neurology 26, 192–195CrossRefGoogle ScholarPubMed
168.Feng, B, et al. (2016) Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling. Scientific Reports 6, 21931Google Scholar
169.Shahrokhi, A, et al. (2014) Association of IL6 single nucleotide polymorphisms with febrile seizures. Journal of the Neurological Sciences 342, 25–28Google Scholar
170.Vezzani, A, et al. (2011) The role of inflammation in epilepsy. Nature Reviews Neurology 7, 31–40Google Scholar