A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns

Singh, Nanda; Charlier, Carole; Stauffer, Dora; DuPont, Barbara R.; Leach, Robin J.; Melis, Roberta; Ronen, Gabriel M.; Bjerre, Ingrid; Quattlebaum, Thomas G.; Murphy, Jerome V.; McHarg, M. L.; Gagnon, Deborah M.; Rosales, Ted; Peiffer, Andy; Anderson, Vernon E.; Leppert, M.

doi:10.1038/ng0198-25

Cited by 1,080 publications

(698 citation statements)

References 32 publications

Supporting

Mentioning

681

Contrasting

Unclassified

Order By: Relevance

“…20 Despite the lack of intron 14 splicing-out, this latter remains in frame with exon 14, over 55 amino-acid residues. The new encoded intracytoplasmic domain, although shorter than that of the canonical KCNQ2 isoform 1 (KCNQ2 wild type (wt)), 19 presents a complete A-domain and a large part of the B-domain described as essential for channel functionality 21 ( Figure 1a and Supplementary information, Figure 1a). Real-time polymerase chain reaction (PCR) performed on human brain cDNAs indicates that splice variant mRNAs represent about 10% of wt channel mRNAs (Supplementary information, Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

“…15 Among the different partners identified to interact with PP2A-Bg, the present study identifies and describes the KCNQ2 potassium channel and two new splice variants. The interest for this particular partner of PP2A-Bg was guided by the following reasons (i) KCNQ2 channel activity is dependent on its state of phosphorylation, 16 (ii) dysfunction of ionic channels associated with pathologies 17 has been observed for several members of the KCNQ family, particularly mutations in KCNQ2 channels are responsible for a peculiar form of epilepsy called benign familial neonatal convulsions (BFNC), 18,19 (iii) a genetic association study indicates that KCNQ2 gene is also linked to BD in one of the two populations we used.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

View full text Add to dashboard Cite

Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

View full text Add to dashboard Cite

show abstract

“…[19][20][21] Other epilepsy syndromes have been shown to be caused by mutations in genes encoding ion channels as well. [22][23][24][25][26][27][28][29] Our families showed autosomal dominant inheritance with high penetrance.…”

Section: Discussionmentioning

confidence: 99%

Benign familial infantile convulsions: a clinical study of seven Dutch families

Callenbach

Coo²,

Vein³

et al. 2002

European Journal of Paediatric Neurology

View full text Add to dashboard Cite

Benign familial infantile convulsions (BFIC) is a recently identified partial epilepsy syndrome with onset between 3 and 12 months of age. We describe the clinical characteristics and outcome of 43 patients with BFIC from six Dutch families and one Dutch-Canadian family and the encountered difficulties in classifying the syndrome. Four families had a pure BFIC phenotype; in two families BFIC was accompanied by paroxysmal kinesigenic dyskinesias; in one family BFIC was associated with later onset focal epilepsy in older generations. Onset of seizures was between 6 weeks and 10 months, and seizures remitted before the age of 3 years in all patients with BFIC. In all, 29 (67%) of the 43 patients had been treated with anti-epileptic drugs for a certain period of time.BFIC is often not recognized as (hereditary) epilepsy by the treating physician. Seizures often remit shortly after the start of anti-epileptic drugs but, because of the benign course of the syndrome and the spontaneous remission of seizures, patients with low seizure frequency do not necessarily have to be treated. If prescribed, anti-epileptic drugs can probably be withdrawn after 1 or 2 years of seizure freedom.

show abstract

“…117 Mutations in these genes were found in the autosomal dominant syndrome benign familial neonatal convulsions (BFNC). 118,119 In addition, mice in which a single copy of the gene for KCNQ2 was disrupted by gene targeting (Kcnq2 ϩ/Ϫ ) showed increased sensitivity to PTZ seizures. 120 The combination of KCNQ2 and KCNQ3 underlies the bulk of the Mcurrent in neurons, 121 although KCNQ5 alone or in combination with KCNQ3 can also contribute to M-current.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

show abstract

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns

Cited by 1,080 publications

References 32 publications

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Benign familial infantile convulsions: a clinical study of seven Dutch families

Molecular Targets for Antiepileptic Drug Development

Contact Info

Product

Resources

About