Complete Loss of the Cytoplasmic Carboxyl Terminus of the KCNQ2 Potassium Channel: A Novel Mutation in a Large Czech Pedigree with Benign Neonatal Convulsions or Other Epileptic Phenotypes

Pereira, Sandrine; Roll, Patrice; Křížová, Jitka; Genton, Pierre; Brázdil, Milan; Kuba, Robert; Cau, Pierre; Rektor, Ivan; Szepetowski, Pierre

doi:10.1111/j.0013-9580.2004.47703.x

Cited by 22 publications

(15 citation statements)

References 27 publications

(39 reference statements)

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“…It was previously believed that BFIS was truly distinct from BFNS based on experimental evidence that some families affected by BFIS link genetically to chromosome 19q, a region not implicated in BFNS, and not to chromosome 20 [12]. It was therefore unexpected to find that some carriers of the KCNQ2 mutation in BFNS families did not have the typical neonatal patterns of seizures, but instead had ages of onset at 3, 4, and 5 months of age, which is consistent with infantile seizures [14,15]. Linkage and haplotype analysis in a Chinese BFIS family supported a possible linkage region at 20q13.3 [18].…”

Section: Discussionmentioning

confidence: 96%

Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2

Zhou

Liu

et al. 2006

Eur J Pediatr

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Sequencing of the KCNQ2 gene revealed that all 17 affected family members carried a heterozygous Gly-to-Val (G271V) mutation in the conserved pore region that resulted from a guanine-to-thymine transition in exon 5 of KCNQ2. The same mutation with a comparable localization in the KCNQ3 (G310V) gene has been found in BFNS patients. The same conserved amino acid was also found to be mutated in the KCNQ1 gene in a family with Long QT Syndrome.

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Section: Discussionmentioning

confidence: 96%

Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2

Zhou

Liu

et al. 2006

Eur J Pediatr

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“…The Szt1 mutation is of particular significance to BFNC because a Czech family with this seizure disorder has been found to possess a genomic deletion of the KCNQ2 C terminus (Pereira et al, 2004). It was shown recently that conditional transgenic overexpression of a dominant-negative Kcnq2 G279S mutation reduces I K(M) amplitude and increases neuronal excitability in mice (Peters et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

Otto¹,

Yang²,

Frankel³

et al. 2006

J. Neurosci.

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The M-type K ϩ current [I K(M) ] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing I K(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor ␣4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on I K(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/؉ and control C57BL/6Jϩ/ϩ mice. Our results show that Szt1 reduces both I K(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal I K(M) , resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.

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“…A few patients of families with typical BFNC may have epileptic seizures with semiology and age of onset consistent with the diagnosis of BIS 59 – 61. Those peculiar “BIS” patients inherited the same KCNQ2 or KCNQ3 mutations as their BFNC relatives, making it possible that the BIS phenotype in these BNFC families is actually due to defects in the KCNQ2/KCNQ3 tetrameric channel.…”

Section: Genetics Of Benign Infantile Seizuresmentioning

confidence: 99%

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes

Rochette

Roll

Szepetowski

2008

Journal of Medical Genetics

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The relationship between paroxysmal movement disorders (PD: paroxysmal dyskinesia) and epilepsy continues to present a challenging problem. Attacks of PD and epileptic seizures have several characteristics in common: both are paroxysmal in nature with a tendency to spontaneous remission, and a subset of PD responds well to anticonvulsants. In 1997, description of the ICCA (infantile convulsions and choreoathetosis) syndrome and linkage to chromosome 16p12-q12 provided the first genetic evidence for common mechanisms shared by benign infantile seizures and PD. The chromosome 16 ICCA locus is by far the most frequently involved in such associations as well as in pure forms of benign infantile seizures. The ICCA region at the pericentromeric area of chromosome 16 shows complicated genomic architecture and the ICCA gene still remains unknown. Genetic studies focusing on PD with or without epilepsy have led to the identification of other genes linked to chromosomes 2q35 and 10q22. Alterations of ion channel and ion pump subunits could provide a simple, albeit probably non-unique, explanation for the pathophysiology of the link between epilepsy and PD. The aim of this review is to update genetic aspects of infantile epileptic seizures and PD and their association in the context of ICCA and ICCA related syndromes.

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Complete Loss of the Cytoplasmic Carboxyl Terminus of the KCNQ2 Potassium Channel: A Novel Mutation in a Large Czech Pedigree with Benign Neonatal Convulsions or Other Epileptic Phenotypes

Cited by 22 publications

References 27 publications

Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2

Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes

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