Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy
ABSTRACT Epilepsy affects more than 0.5% of the world's population and has a large genetic component. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.
Full-textDOI: · Available from: Valentin Stein, Feb 08, 2015
- SourceAvailable from: Maurizio Taglialatela
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- "All missense mutations and functional consequences have been studied for five of them; four of them (p.Glu299Lys, p.Asp305Gly, p.Trp309Arg, and p.Gly310Val) are located in the pore region of Q3 and the fifth one (p.Arg330Cys) immediately before S6. Functional analyses in Xenopus oocytes showed that Q3 subunits carrying the p.Gly310Val and p.Asp305Gly mutation caused a 20% and 40% reduction, respectively , in the maximal current of heteromeric Q2/Q3 channels [Schroeder et al., 1998; Singh et al., 2003], whereas the Q3 p.Trp309Arg mutation was found to reduce by over 60% the Q2/Q3 heteromeric channel currents in HEK293 cells, suggesting a dominant negative effect [Uehara et al., 2008; Sugiura et al., 2009]. "
ABSTRACT: Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, EEG suppression-burst pattern (Ohtahara syndrome) and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy". In the present paper, we describe clinical, genetic and functional data from 17 patients/families whose electro-clinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three ins/del and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly-found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. This article is protected by copyright. All rights reserved.Human Mutation 12/2013; DOI:10.1002/humu.22500 · 5.05 Impact Factor
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- "Indeed, blockade of M-currents is associated with depolarization of the resting membrane potential, and generation of trains of action potentials (Brown and Adams, 1980; Delmas and Brown, 2005). Mutations in KCNQ2 or KCNQ3 cause a form of juvenile epilepsy called benign familial neonatal convulsions (Biervert et al., 1998; Charlier et al., 1998; Schroeder et al., 1998; Singh et al., 1998, Table 1). The clinical features of KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) are characterized by tonic or apneic episodes, focal clonic activity, or autonomic changes that start between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12 th month. "
ABSTRACT: K(+) channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K(+) channels as primary targets of genetic variations or perturbations in K(+)-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K(+) channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K(+) channels defects underlying distinct epilepsies as "K(+) channelepsies," and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K(+) channel classification, which could be also adopted to easily identify other channelopathies involving Na(+) (e.g., Nav x.y-phenotype), Ca(2+) (e.g., Cav x.y-phenotype), and Cl(-) channels. Furthermore, we discuss novel genetic defects in K(+) channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K(+) channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.Frontiers in Cellular Neuroscience 09/2013; 7:134. DOI:10.3389/fncel.2013.00134 · 4.18 Impact Factor
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- "s - sium channels ( Brown and Passmore , 2009 ) . Four of these genes ( KCNQ2 - 5 ) are expressed in the central nervous system both on RNA and protein level ( Brown and Passmore , 2009 ) and are there - fore excellent candidate susceptibility genes for a wide range of neuronal disorders . K V 7 . 3 forms heterotetrameric channels with K V 7 . 2 ( Schroeder et al . , 1998 ) , K V 7 . 4 ( Kubisch et al . , 1999 ) , and K V 7 . 5 ( Schroeder et al . , 2000 ) . K V 7 . 2 / K V 7 . 3 heteromeric channels primarily localize at the axon initial segment ( AIS ) and under - lie the M - current involved in regulation of neuronal excitability ( Wang et al . , 1998 ; Schroeder et al . , 2000 ) ."
ABSTRACT: Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.Frontiers in Genetics 04/2013; 4:54. DOI:10.3389/fgene.2013.00054