Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man

Alekov, Alexi K.; Rahman, Mozibur; Mitrović, Nenad; Lehmann‐Horn, Frank; Lerche, Holger

doi:10.1046/j.0953-816x.2001.01590.x

Cited by 63 publications

(33 citation statements)

References 32 publications

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“…Various functional effects of the GEFSϩ mutations in SCN1A have been suggested (Alekov et al, 2001;Spampanato et al, 2001;Lossin et al, 2002Lossin et al, , 2003. For the SCN1B mutation, co expression of the ␤1 subunit harboring the GEFSϩ mutation with the ␣ subunit showed slowed inactivation, suggesting an increment of Na ϩ currents in patients (Wallace et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Kamiya¹,

Kaneda²,

Sugawara³

et al. 2004

J. Neurosci.

186

146

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Mutations, exclusively missense, of voltage-gated sodium channel ␣ subunit type 1 (SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and frameshift mutations of SCN1A, by contrast, were identified in intractable epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first nonsense mutation of SCN2A in a patient with intractable epilepsy and severe mental decline. The phenotype is similar to SMEI but distinct because of partial epilepsy, delayed onset (1 year 7 months), and absence of temperature sensitivity. A mutational analysis revealed that the patient had a heterozygous de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na v 1.2 wild-type channels and the R102X mutant protein coexpressed in human embryonic kidney 293 cells showed that the truncated mutant protein shifted the voltage dependence of inactivation of wild-type channels in the hyperpolarizing direction. Analysis of the subcellular localization of R102X truncated protein suggested that its dominant negative effect could arise from direct or indirect cytoskeletal interactions of the mutant protein. Haploinsufficiency of Na v 1.2 protein is one plausible explanation for the pathology of this patient; however, our biophysical findings suggest that the R102X truncated protein exerts a dominant negative effect leading to the patient's intractable epilepsy.

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Section: Discussionmentioning

confidence: 99%

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Kamiya¹,

Kaneda²,

Sugawara³

et al. 2004

J. Neurosci.

186

146

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“…To correlate clinical phenotypes with the underlying sodium channel disorder, we and others have characterized the biophysical properties of various mutant voltage-gated sodium channels associated with epilepsy (18)(19)(20)(29)(30)(31)(32)(33). Early findings have suggested that in some cases of GEFSϩ, SCN1A mutations promote a gain of function, whereas mutations associated with SMEI disable channel function.…”

Section: Discussionmentioning

confidence: 99%

Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

Rhodes

Lossin

Vanoye

et al. 2004

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

164

171

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Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel ␣1 subunit (NaV1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using wholecell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent, noninactivating channel activity resembling the pattern of channel dysfunction observed for alleles associated with generalized epilepsy with febrile seizures plus. Our data provide evidence for a range of SCN1A functional abnormalities in SMEI, including gain-of-function defects that were not anticipated in this disorder. Our results further indicate that a complex relationship exists between phenotype and aberrant sodium channel function in these inherited epilepsies.seizure ͉ generalized epilepsy with febrile seizures plus ͉ SCN1A ͉ electrophysiology M utations in genes encoding neuronal voltage-gated sodium channels have been linked to inherited forms of epilepsy. Genetic defects in two pore-forming ␣ subunits (encoded by SCN1A and SCN2A) and the accessory ␤ 1 subunit (encoded by SCN1B) have been discovered in four distinguishable clinical syndromes with overlapping features (1-6). Generalized epilepsy with febrile seizures plus (GEFSϩ) is an autosomal dominant disorder characterized by childhood febrile seizures that persist beyond age 6 years, as well as afebrile generalized or partial seizures of various types. In 1998, Wallace et al.(1) described a single missense mutation in SCN1B, the gene encoding the voltage-gated sodium channel ␤ 1 subunit, in a large GEFSϩ pedigree. However, SCN1B mutations are rare causes of GEFSϩ (7,8). By contrast, mutations in SCN1A, the gene encoding the neuronal sodium channel ␣-subunit Na V 1.1, have been identified in several GEFSϩ families (2, 9-11).SCN1A mutations occur also in severe myoclonic epilepsy of infancy (SMEI), a rare convulsive disorder characterized by febrile seizures with onset during the first year of life, followed by intractable epilepsy, impaired psychomotor development, and ataxia (12, 13). Seizures in this disorder typically do not respond to standard anticonvulsant pharmacotherapy. More than 80 heterozygous, predominantly de novo, SCN1A mutations have been reported in this disorder (3,(14)(15)(16)(17). Because many of the SCN1A mutations discovered in SMEI probands are nonsense and frameshift alleles, loss of neuronal sodium channel function as the cause of this syndrome seems most plausible. This hypothesis is supported by the observation that certain missense mutations in this condition render SCN1A channels nonfunctional or severely impair...

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“…Alekov et al introduced R1648H into the SCN4A cDNA and expressed the clone in mammalian HEK tsA201 cells. In this context, they observed slowed inactivation and accelerated recovery from inactivation, leading to increased channel availability, but no persistent current (42). A second substitution at the same residue, R1648C, was identified in a patient with SMEI (47).…”

Section: Figurementioning

confidence: 99%

“…Functional effects of SCN1A missense mutations Twenty SCN1A missense mutations have been evaluated in functional assays (23,24,33,(39)(40)(41)(42)(43)(44)(45)(46). Functional analysis is complicated by the difficulty of cloning neuronal sodium channel cDNAs, which are uniquely unstable during propagation in bacterial cultures (unlike the muscle sodium channel cDNAs or the calcium and potassium channel cDNAs).…”

Section: Figurementioning

confidence: 99%

Sodium channel mutations in epilepsy and other neurological disorders

Meisler

Kearney

2005

Journal of Clinical Investigation

450

367

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Since the first mutations of the neuronal sodium channel SCN1A were identified 5 years ago, more than 150 mutations have been described in patients with epilepsy. Many are sporadic mutations and cause loss of function, which demonstrates haploinsufficiency of SCN1A. Mutations resulting in persistent sodium current are also common. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sensitivity to pain, respectively. The rapid pace of discoveries suggests that sodium channel mutations are significant factors in the etiology of neurological disease and may contribute to psychiatric disorders as well.

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Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man

Cited by 63 publications

References 32 publications

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

A Nonsense Mutation of the Sodium Channel GeneSCN2Ain a Patient with Intractable Epilepsy and Mental Decline

Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy

Sodium channel mutations in epilepsy and other neurological disorders

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