Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction

Richards, Michaella C.

doi:10.1136/jmg.2003.013938

Cited by 66 publications

(43 citation statements)

References 37 publications

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“…GST-Kv7.2 Helices A-B fusion protein carrying the K526N mutation was purified. Other mutations, (A343D, I340E in helix A and S511D in helix B), known to disrupt CaM binding [6], or to cause BFNE (R353G) [15,35], were used as negative controls, (Figure 4(a)). We also examined two CaM binding proteins fused to GST as positive controls for the interaction in the presence (the C-terminus of the NMDA receptor, NR1a) or absence (neurogranin) of Ca 2+ [6,18].…”

Section: Resultsmentioning

confidence: 99%

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

et al. 2018

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Heteromers of Kv7.2/Kv7.3 subunits constitute the main substrate of the neuronal M-current that limits neuronal hyper-excitability and firing frequency. Calmodulin (CaM) binding is essential for surface expression of Kv7 channels, and disruption of this interaction leads to diseases ranging from mild epilepsy to early onset encephalopathy. In this study, we addressed the impact of a charge neutralizing mutation located at the periphery of helix B (K526N). We found that, CaM binding and surface expression was impaired, although current amplitude was not altered. Currents were reduced at a faster rate after activation of a voltage-dependent phosphatase, suggesting that phosphatidylinositol-4,5-bisphosphate (PIP2) binding was weaker. In contrast, a charge neutralizing mutation located at the periphery of helix A (R333Q) did not affect CaM binding, but impaired trafficking and led to a reduction in current amplitude. Taken together, these results suggest that disruption of CaM-dependent or CaM-independent trafficking of Kv7.2/Kv7.3 channels can lead to pathology regardless of the consequences on the macroscopic ionic flow through the channel.

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Section: Resultsmentioning

confidence: 99%

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

et al. 2018

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“…The data reveal that the pathogenic L609R mutation [equivalent to L637R in the long Kv7.2 splice variant (Richards et al, 2004)] destabilizes the helix D-dependent tetramerization of the C-terminal region of Kv7.2. In addition, this mutation reduces the apparent affinity for CaM binding, and leads to increased resistance to the action of a voltage-dependent phosphatase that reduces PIP 2 concentration at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Defects in channel-PIP 2 sensitivity through interfering mutations can lead to disease (Logothetis et al, 2010). It is attractive to hypothesize that mutations not located at the binding site that disrupt channel-PIP 2 dependency, such as L609R described here and which was found in a patient with an epileptic condition (Richards et al, 2004), could also lead to disease.…”

Section: Discussionmentioning

confidence: 99%

“…We studied next the consequences of the helix D L609R mutation [equivalent to L637R in the long Kv7.2 splice variant (Richards et al, 2004)] found in patients with hereditary benign familial convulsions (Richards et al, 2004), which is predicted to interrupt coiled-coil formation (Lupas and Gruber, 2005;Schwake et al, 2006) (Fig. 1B).…”

Section: The Helix D L609r Mutation Disrupts Coiled-coil Formationmentioning

confidence: 99%

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Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Alberdi

Gomis-Pérez

Bernardo‐Seisdedos

et al. 2015

Journal of Cell Science

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We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how an ion channel is regulated by a membrane lipid. Our data reveal that regulation by phosphatidylinositol(4,5)bisphosphate (PIP 2 ) and stabilization of assembled Kv7.2 subunits by intracellular coiled-coil regions far from the membrane are coupled molecular processes. Live-cell fluorescence energy transfer measurements and direct binding studies indicate that remote coiled-coil formation creates conditions for different CaM interaction modes, each conferring different PIP 2 dependency to Kv7.2 channels. Disruption of coiledcoil formation by epilepsy-causing mutation decreases apparent CaM-binding affinity and interrupts CaM influence on PIP 2 sensitivity.

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“…Hence, according to these results, CaM is potentially involved in the BFNS pathogenesis. KCNA1 (Kv1.1) is another interesting epilepsy-susceptibility gene, a member (1) of shaker-related subfamily that appears mutated in episodic ataxia type 1 (EA1 with myokymia) [111], a rare autosomal dominant disorder frequently associated with an increased incidence of epilepsy [112].…”

Section: Gene Mutations Voltage-and Ligand-gated Ion Channels and Epmentioning

confidence: 99%

Targeted Resequencing of Epilepsy Genes: A Pharmaco-Therapeutic Perspective

Moles¹,

Romanelli²,

Zara³

et al. 2014

Int J Neurorehabilitation Eng

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More than half of all epilepsies have some genetic basis and single gene defects in ion channels or neurotransmitter receptors are associated with some inherited forms of epilepsy. Genetic research even in the field of epilepsy disorders is increasing in term of testing platform for the investigation of sequence and structural variation. Next generation sequencing (NGS), i.e., high-throughput sequencing technologies now allow analyses that were previously prohibitive. Targeted resequencing methods by diagnostic panels enable to sequence all the genes associated with a certain disease simultaneously within a few weeks. In this review, we will discuss the overall helpfulness and convenience of simultaneous genotyping of multiple epilepsy genes by NGS in a pharmacogenetics perspective.

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Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction

Cited by 66 publications

References 37 publications

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation

Targeted Resequencing of Epilepsy Genes: A Pharmaco-Therapeutic Perspective

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