A Potassium Channel Mutation in Neonatal Human Epilepsy

Biervert, Christian; Schroeder, Björn C.; Kubisch, Christian; Berkovic, Samuel F.; Propping, Peter; Jentsch, Thomas J.; Steinlein, Ortrud K.

doi:10.1126/science.279.5349.403

Cited by 989 publications

(744 citation statements)

References 23 publications

Supporting

Mentioning

710

Contrasting

Unclassified

Order By: Relevance

“…Seizures in these individuals usually start around day 3 post-natal and disappear in 85-90% of the patients after a few months and only 10-15% of the patients display seizures later in childhood. 18 Both results presented in this work for KCNQ2 and recent data implicating KCNQ3 39 that can also be mutated in BFNC 38 plead for the interest of such a clinical investigation.…”

Section: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 62%

“…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: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 62%

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

“…In a broader sense the AOB, because it has a simple structure, is a CNS region that may facilitate the study of memory. Since acetylcholine in the CNS is associated with memory disorders such as Alzheimer's disease, and the KCNQ channel in the CNS is associated with epileptic disorders such as benign familial neonatal convulsions (Biervert et al, 1998), understanding the precise mechanism underlying the synaptic plasticity evident in our system may greatly increase both the understanding of, and the therapeutic options for, these debilitating diseases.…”

Section: Resultsmentioning

confidence: 99%

Muscarinic receptor type 1 (M1) stimulation, probably through KCNQ/Kv7 channel closure, increases spontaneous GABA release at the dendrodendritic synapse in the mouse accessory olfactory bulb

Takahashi

Kaba

2010

Brain Research

View full text Add to dashboard Cite

Cholinergic modulation of spontaneous GABAergic currents (mIPSC) was studied using whole-cell patch methods in mouse accessory olfactory bulb slices. Carbachol (above 100 !M) administration produced an increase in the mIPSC frequency in mitral cells, but did not affect the responses of mitral cells to GABA. The carbachol effect persisted in the presence of combined ionotropic and metabotropic glutamatergic receptor antagonists. The carbachol effect was reduced by the muscarinic receptor type-1 and -4 (M1, M4) antagonist pirenzepine (10 !M), but not by the M2 and M4 antagonist himbacine (10 !M). The KCNQ/Kv7 potassium channel openers retigabine (80 !M) and diclofenac (300 !M) blocked the carbachol action, while the KCNQ potassium channel blocker XE-911 (20 !M) increased the mIPSC frequency. XE-911's action persisted in the presence of glutamate receptor blockers. In the presence of carbachol, mIPSCs were abolished by Ni (200 !M), while being insensitive to the calcium channel blocker nimodipine (30 !M), suggesting a role for R-type calcium channels in the GABA release. These results suggest that carbachol closed KCNQ channels by stimulating M1 receptors on granule cell dendrites, and the resulting depolarized and unstable membrane promoted calcium influx, thus increasing the GABA release. The possible role of acetylcholine in facilitating formation of a pheromone memory in mice is also discussed. Classification TermsSection: Neurophysiology

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

A Potassium Channel Mutation in Neonatal Human Epilepsy

Cited by 989 publications

References 23 publications

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

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

Muscarinic receptor type 1 (M1) stimulation, probably through KCNQ/Kv7 channel closure, increases spontaneous GABA release at the dendrodendritic synapse in the mouse accessory olfactory bulb

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

Contact Info

Product

Resources

About