Spectrum of<i>SCN1A</i>mutations in severe myoclonic epilepsy of infancy

Nabbout, Rima; Gennaro, Elena Di; Bernardina, Bernardo Dalla; Dulac, Olivier; Madia, Francesca; Bertini, Enrico; Capovilla, Giuseppe; Chiron, Catherine; Cristofori, G.; Elia, Maurizio; Fontana, Elena; Gaggero, R.; Granata, Tiziana; Guerrini, Renzo; Loi, Mario; Selva, L. La; Lispi, Maria Luisa; Matricardi, Alberto; Romeo, Antonino; Tzolas, V.; Valseriati, Daniela; Veggiotti, Pierangelo; Vigevano, Federico; Vallée, Louis; Bricarelli, Franca Dagna; Bianchi, Amedeo; Zara, Federico

doi:10.1212/01.wnl.0000069463.41870.2f

Cited by 241 publications

(174 citation statements)

References 28 publications

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“…Interestingly, mortality rate in heterozygous mice varied with genetic background. The importance of genetic background, or modifier genes, has been also suggested in some familial SMEI cases in which SMEI patients have inherited the SCN1A mutations from mildly affected parents Nabbout et al, 2003;Meisler and Kearney, 2005;Yamakawa, 2005).…”

Section: Discussionmentioning

confidence: 99%

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Ogiwara¹,

Miyamoto²,

Morita³

et al. 2007

J. Neurosci.

799

908

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Loss-of-function mutations in human SCN1A gene encoding Na v 1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Na v 1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Na v 1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.

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Section: Discussionmentioning

confidence: 99%

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Ogiwara¹,

Miyamoto²,

Morita³

et al. 2007

J. Neurosci.

799

908

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“…Most SMEI mutations arose de novo, but in few cases, they have been inherited from mildly affected parents (Claes et al, 2001;Nabbout et al, 2003). A family history of epilepsy has been reported for some SMEI cases, and it has been proposed to extend the GEFSϩ spectrum including SMEI as the most severe phenotype (Singh et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

110

111

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Familial epilepsies are often caused by mutations of voltage-gated Na ϩ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na v 1.1 (SCN1A) Na ϩ channel ␣ subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature Ͻ30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na ϩ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.

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“…In contrast, most SCN1A mutations that have been identified in SMEI are predicted to result in null alleles or reduced protein levels (Claes et al, 2001Sugawara et al, 2001b;Ohmori et al, 2002;Fujiwara et al, 2003;Nabbout et al, 2003;Wallace et al, 2003). The severity of clinical disorders resulting from mutations in SCN1A thus varies from mild to severe, with the most severe phenotype generally resulting from decreased sodium channel activity as in SMEI.…”

Section: Discussionmentioning

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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Spectrum ofSCN1Amutations in severe myoclonic epilepsy of infancy

Cited by 241 publications

References 28 publications

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

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Spectrum ofSCN1Amutations in severe myoclonic epilepsy of infancy

Cited by 241 publications

References 28 publications

Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

An Epilepsy Mutation in the Sodium ChannelSCN1AThat Decreases Channel Excitability

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Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Na_v1.1 Na⁺Channel Mutant