A deletion in
            <i>SCN1B</i>
            is associated with febrile seizures and early-onset absence epilepsy

Audenaert, Dominique; Claes, Lieve; Ceulemans, Berten; Löfgren, A.; Broeckhoven, Christine Van; Jonghe, Peter De

doi:10.1212/01.wnl.0000080362.55784.1c

Cited by 149 publications

(107 citation statements)

References 10 publications

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“…Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12,13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14)(15)(16)(17)(18)(19)(20)(21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactions in vitro (11).…”

mentioning

confidence: 72%

“…Given that Scn1b mutations result in channelopathies in vivo (12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and that β1-mediated neurite outgrowth in CGNs requires I Na and Na v 1.6, we postulated that β1 might regulate electrical excitability in the cerebellum. To test this, we recorded APs in P12-13 WT and Scn1b null CGNs in cerebellar slices by whole-cell patch clamping.…”

Section: Resultsmentioning

confidence: 99%

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Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

159

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Voltage-gated Na + channel (VGSC) β1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na + current (I Na ) mediated by Na v 1.6. In addition, β1 is required for highfrequency action potential firing. Transient I Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I Na , thought to underlie high-frequency firing in Na v 1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na v 1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v 1.6 at the AIS, we observed an increase in Na v 1.1, whereas Na v 1.2 was unchanged. This indicates that β1 is required for normal localization of Na v 1.6 at the AIS during the postnatal developmental switch to Na v 1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na v 1.6 such that β1-mediated neurite outgrowth requires Na v 1.6-mediated I Na , and Na v 1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.V oltage-gated Na + channels (VGSCs), composed of one poreforming α subunit and two β subunits (1), are responsible for initiation and conduction of action potentials (APs) (2). Of the nine α subunits (3), Na v 1.1, Na v 1.2, and Na v 1.6 are found in the postnatal CNS (4, 5) where they display developmentally regulated expression patterns in specialized neuronal subcellular domains. For example, Na v 1.1 and Na v 1.2 are replaced during postnatal development at the axon initial segment (AIS) and nodes of Ranvier by Na v 1.6. Scn8a null mice display motor dysfunction, ataxia, and lethality by postnatal day (P) 21, suggesting that this developmental switch to Na v 1.6 expression in brain is critical (6, 7). Scn8a null retinal ganglion neurons display impaired excitability, demonstrating that Na v 1.6 is vital for high-frequency firing (8-10). Thus, VGSC-driven neuronal activity is important for proper CNS development, although the underlying mechanism(s) are not well understood.VGSC β1 subunits are multifunctional molecules that modulate channel kinetics and gating, regulate channel cell surface expression, and participate in cell-cell adhesion in vitro (11). Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12, 13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14-21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactio...

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mentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

159

View full text Add to dashboard Cite

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“…In vivo, ␤1 also modulates electrical excitability: Scn1b null mice are ataxic and display spontaneous generalized seizures . Mutations in SCN1B result in human brain disease, including generalized epilepsy with febrile seizures plus and temporal lobe epilepsy (Wallace et al, 1998(Wallace et al, , 2002Meadows et al, 2002;Audenaert et al, 2003;Scheffer et al, 2007). VGSC ␤ subunits are unique among ion channel auxiliary subunits in that they also function as immunoglobulin superfamily cell adhesion molecules (IGSFCAMs), directing VGSC insertion into the plasma membrane, interacting with other signaling proteins, and participating in adhesion in vitro (Isom et al, 1994;Isom and Catterall, 1996).…”

Section: Introductionmentioning

confidence: 99%

Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

Brackenbury¹,

Davis²,

Chen³

et al. 2008

J. Neurosci.

176

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Voltage-gated Naϩ channel ␤1 subunits are multifunctional, participating in channel modulation and cell adhesion in vitro. We previously demonstrated that ␤1 promotes neurite outgrowth of cultured cerebellar granule neurons (CGNs) via homophilic adhesion. Both lipid raft-associated kinases and nonraft fibroblast growth factor (FGF) receptors are implicated in cell adhesion molecule-mediated neurite extension. In the present study, we reveal that ␤1-mediated neurite outgrowth is abrogated in Fyn and contactin (Cntn) null CGNs. ␤1 protein levels are unchanged in Fyn null brains, whereas levels are significantly reduced in Cntn null brain lysates. FGF or EGF (epidermal growth factor) receptor kinase inhibitors have no effect on ␤1-mediated neurite extension. These results suggest that ␤1-mediated neurite outgrowth occurs through a lipid raft signaling mechanism that requires the presence of both fyn kinase and contactin. In vivo, Scn1b null mice show defective CGN axon extension and fasciculation indicating that ␤1 plays a role in cerebellar microorganization. In addition, we find that axonal pathfinding and fasciculation are abnormal in corticospinal tracts of Scn1b null mice consistent with the suggestion that ␤1 may have widespread effects on postnatal neuronal development. These data are the first to demonstrate a cell-adhesive role for ␤1 in vivo. We conclude that voltage-gated Na ϩ channel ␤1 subunits signal via multiple pathways on multiple timescales and play important roles in the postnatal development of the CNS.

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“…The febrile seizures associated with GEFSϩ can persist beyond 6 years of age and phenotypically may be simple or complex (Scheffer and Berkovic, 1997). Recent studies have demonstrated a role for the involvement of three voltage-gated sodium channel genes, SCN1A (Escayg et al, 2000Wallace et al, 2001a), SCN1B (Wallace et al, 1998;Audenaert et al, 2003), and SCN2A (Sugawara et al, 2001a), and the GABA A receptor genes GABRG2 (Baulac et al, 2001;Wallace et al, 2001b) and GABRD (Dibbens et al, 2004) in the pathogenesis of GEFSϩ. Only a small number of GEFSϩ mutations have been identified, of which SCN1A accounts for the largest proportion, with 15 mutations reported to date.…”

Section: Introductionmentioning

confidence: 99%

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

et al. 2006

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Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABA A receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFSϩ). A novel mutation, R859C, in the Na v 1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFSϩ. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Na v 1.1 channel ␣ subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Na v 1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFSϩ sodium channel mutations, which have changes predicted to increase neuronal firing.

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A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy

Cited by 149 publications

References 10 publications

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

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A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy

Cited by 149 publications

References 10 publications

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Voltage-Gated Na+Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

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Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo