ReviewIon channel variation causes epilepsies
Introduction
Epilepsy is a group of diseases caused by a non-controlled discharge of neurons of either the whole cortex (generalized epilepsies) or localized brain areas (partial epilepsies). Both generalized and partial epilepsies may be caused by detectable (symptomatic) or hypothetical (cryptogenic) structural or metabolic abnormalities of the brain. Often, however, no such abnormalities can be observed and these epilepsies called idiopathic are supposed to be caused by defects of one or several genes. In addition to this internationally recognized classification (ILAE, 1989) one can broadly divide epilepsies into those displaying a Mendelian mode of inheritance and those with a more complex pattern of transmission.
Several genes coding for proteins with very different rarely known or hypothetical functions have been identified in the group of Mendelian symptomatic epilepsies. Despite the interest of these discoveries the goal of this report is not to detail them. A more homogenous picture arises in the field of the Mendelian idiopathic epilepsies that recently emerged as channelopathies. Indeed, three types of epilepsies have been linked to mutations in human genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR) (α4, CHRNA4, and β2, CHRNB2, subunits), the voltage-gated potassium (KCNQ2, KCNQ3) and the voltage-gated sodium (SCN1A, SCN1B) channels.
Mutations in CHRNA4 and CHRNB2 are associated with some cases of familial epilepsies classified as autosomal dominant nocturnal frontal lobe epilepsies (ADNFLE) with incomplete penetrance [9], [27]. This epilepsy is characterized by nocturnal motor seizures initiating in the frontal lobe, with an important intra and interfamilial clinical heterogeneity [22].
Generalized epilepsy with febrile seizures ‘plus’ (GEFS+) is a relatively benign autosomal dominant epileptic syndrome. GEFS+ combines several types of seizures: febrile convulsions that can persist past the age of 6 years, and afebrile seizures such as generalized tonic-clonic seizures, absences, partial seizures, sometimes myoclonic-astatic epilepsy. The first GEFS+ gene identified was SCN1B, coding for the accessory subunit β1 of the voltage-gated sodium channel [30].
Mutations in voltage-gated potassium channels KCNQ2 and KCNQ3 have been identified in benign familial neonatal convulsions (BFNC) [4], [25], a rare autosomal dominant epileptic syndrome beginning in the first days of life, and relapsing within a few weeks or months. Sometimes (in roughly 15% of BFNC cases), seizures persist in adulthood. To date, 17 KCNQ2 mutations, of several types, have been identified, spanning the entire gene, and no recurrent mutations have been observed. On the contrary, only two different missense mutations have been reported in KCNQ3, a KCNQ2 homologous gene, in two BFNC pedigrees [7], [15]. This mutational diversity does not seem to correspond to the clinical heterogeneity.
Thus, even rare, the Mendelian idiopathic epilepsies may help us to elaborate the inventory of the main genes responsible for these diseases and to understand how they intervene in the pathophysiological process. The several naturally occurring mutations, responsible for seizures in murine models and affecting genes coding for ion channel subunits, will also certainly be useful in this perspective.
At present, we are, however, far from this final goal. The first reason is that the majority of idiopathic epilepsies display a complex non-Mendelian pattern of inheritance. Today, the responsible genes remain unknown and we are still unable to determine if variants of the Mendelian idiopathic epilepsies related genes are involved in the susceptibility to these neurological diseases. The second reason is that the functional studies of mutations responsible for Mendelian idiopathic epilepsies are just beginning and are still limited to their molecular consequences (at the cellular level). Understanding how these mutations engender the disorders at the cellular and control levels of the neuronal network are the next challenges.
In this work we report our results obtained by the collaboration of a clinical and a basic research group in this emerging field of epilepsy genetics and channelopathies.
Section snippets
Pattern of nAChR subunits gene expression in human brain
Concurrently to the molecular, pharmacological and functional studies, it is also important to establish the expression pattern of the genes reported to be associated with human idiopathic epilepsies in order to understand their role in epilepsies. However, up to few years ago, little was known about the distribution of these genes in the human brain, mainly due to the limitations to obtain human tissues. As a first step, we investigated the regional and cellular distribution of α4, α7 and β2
Discussion
Epilepsy is a common neurological disease that strikes roughly 1% of the population and encompasses a variety of disorders with EEG paroxysms. Despite of a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remain poorly understood. Linkage analysis and positional cloning tools have not been sufficient to determine the pathogenic mechanisms of common idiopathic epilepsies, and hence, novel approaches, based on the etiology of epilepsy, are necessary.
Acknowledgments
These studies were made possible thanks to the kind collaboration of J. Mulley and S. Berkovic who provided genomic DNAs. We thank O. Steinlein for providing α4 and β2 cDNAs. We thank V. Itier for useful comments and discussion. This work was supported to D.B. and A.M. by the Swiss National Science Foundation PNR38 4038-044050
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Transcriptome of the Wistar audiogenic rat (WAR) strain following audiogenic seizures
2018, Epilepsy ResearchCitation Excerpt :This gene encodes a subunit of the nicotinic acetylcholine receptor (nAChR) that is permeable to cations and leads to depolarization of the plasma membrane leading to a postsynaptic excitatory potential (Becchetti et al., 2015; Ghasemi and Hadipour-Niktarash, 2015). Mutations in Chrna4 are associated with nocturnal frontal lobe epilepsy (Hirose et al., 1999; Leniger et al., 2003; Steinlein et al., 1995, 1997) and febrile seizures (Chou et al., 2003) and were related to increasing the receptors sensitivity to acetylcholine, reduce calcium permeability and rapid desensitization of nAChR (Bertrand et al., 2002; Combi et al., 2004; Kuryatov et al., 1997; Moulard et al., 2001; Weiland et al., 1996). It is believed that the reduction of nAChR activity may disrupt the balance between neuronal excitation and inhibition (Kuryatov et al., 1997).
Structure of a Ca<sup>2 +</sup>/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation
2013, Journal of Molecular BiologyCitation Excerpt :In accordance with the buried nature of this position, the M520R change has been reported to disrupt both channel function and CaM binding.51 Two Kv7.2 mutations, R533Q26,52 and K562N,53 correspond to Kv7.4 positions Arg547 and Lys548 (Fig. 4b) that make electrostatic interactions with Ca2 +/N-lobe residues Glu54 and Asp50, respectively (Fig. 4e), and would disrupt these electrostatic contacts. The fourth reported mutant, Kv7.1 A525T,54 corresponds to Kv7.4 Ala545, a residue having no contacts with Ca2 +/CaM (Supplementary Fig. S4).
Naturally occurring carboxypeptidase A6 mutations: Effect on enzyme function and association with epilepsy
2012, Journal of Biological ChemistryCitation Excerpt :Both gain-of-function (31, 32) and loss-of-function (33–35) mutations of other genes have been found to cause epilepsy. We expect that both types of mutations in CPA6 could lead to epilepsy; however, in vitro experiments present difficulties in discriminating between the two, as it is not always clear how these mutations will affect the human brain in vivo (36). Generally, common variations in the CPA6 gene were not found to markedly reduce the activity or expression of the enzyme and were not found to be associated with epilepsy.
Calmodulin activation limits the rate of KCNQ2 K<sup>+</sup> channel exit from the endoplasmic reticulum
2009, Journal of Biological ChemistryCitation Excerpt :The induction of conformational changes to 12.5 nm D-CaM was studied in vitro using GST fusion proteins containing helices A and B of KCNQ2 (GST-Q2AB; Figs. 1 and 2). The impact of several mutations in helix A of KCNQ2 was examined, including two that cause BFNC in humans (L339R and R353G) (10, 11). Virtually no difference in fluorescence was observed when the interaction between D-CaM and the reference A343D and I340E mutants was assayed, although the two mutants linked to BFNC and the I340A mutant produced a moderate effect on the maximal fluorescence emission (Fig. 2 and Table 1).