Two Novel SCN1A Missense Mutations in Generalized Epilepsy with Febrile Seizures Plus

Annesi, Grazia; Gambardella, Antonio; Carrideo, Sara; Incorpora, Gemma; Labate, Angelo; Pasqua, Angela Aurora; Civitelli, Donatella; Polizzi, Agata; Annesi, Ferdinanda; Spadafora, Patrizia; Tarantino, Patrizia; Candiano, Innocenza Claudia Cirò; Romeo, Nelide; Marco, Elvira Valeria De; Ventura, Paolo; LePiane, Emilio; Zappia, Mario; Aguglia, Umberto; Pavone, Lorenzo; Quattrone, Aldo

doi:10.1046/j.1528-1157.2003.22503.x

Cited by 51 publications

(40 citation statements)

References 6 publications

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“…This effect is analogous to that of many SMEI mutations that cause truncations and consequently complete loss of function of Nav1.1, the haploinsufficiency of which generates seizures probably by decreasing excitability of GABAergic neurons, as observed in Na v 1.1 knock-out mice (Yu et al, 2006). Therefore, hNa v 1.1-M1841T is a loss of function mutant that can cause the SMEI phenotype observed in one member of the GEFSϩ family (Annesi et al, 2003).…”

Section: Discussionmentioning

confidence: 60%

“…Our data show that the mutation M1841T of Na v 1.1 Na ϩ channel, identified in a GEFSϩ family with a particularly large phenotypic spectrum ranging from mild FSϩ to SMEI (Annesi et al, 2003), causes a complete loss of function of Na v 1.1, similarly to other described GEFSϩ mutations (Lossin et al, 2003). This effect is analogous to that of many SMEI mutations that cause truncations and consequently complete loss of function of Nav1.1, the haploinsufficiency of which generates seizures probably by decreasing excitability of GABAergic neurons, as observed in Na v 1.1 knock-out mice (Yu et al, 2006).…”

Section: Discussionmentioning

confidence: 62%

“…The ␣ subunit consists of four homologous domains (I-IV), each formed by six transmembrane segments (S1-S6) and N-terminal and C-terminal cytoplasmic domains; the S4 segments are the positively charged voltage sensors, the S5 and S6 segments of each homologous domain and the re-entrant loops between them form the pore (Catterall, 2000). The GEFSϩ M1841T mutation of Na v 1.1 ␣ subunit (Annesi et al, 2003) that we studied is depicted as a black circle. ␤ subunits are related proteins with a large extracellular Ig-like domain, a single transmembrane segment and a short cytoplasmic C-terminal region; the Ig-like domain is stabilized by an intramolecular disulfide bridge (Catterall, 2000;Isom, 2001).…”

Section: Methodsmentioning

confidence: 99%

“…1). The mutation cosegregates with epileptic seizures in a GEFSϩ family whose affected members show extreme phenotypes, ranging from simple febrile convulsions in the mildest case to SMEI in the most severe one (Annesi et al, 2003). Thus, the study of this mutation could shed light on the mechanism of the phenotypic variability in epilepsies caused by mutations of Na ϩ channels.…”

Section: Introductionmentioning

confidence: 99%

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

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

108

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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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Rusconi¹,

Scalmani²,

Cassulini³

et al. 2007

J. Neurosci.

108

111

View full text Add to dashboard Cite

show abstract

“…However, five isolated patients and an affected sib pair with have been reported in which an SCN1A mutation was inherited from an asymptomatic or mildly affected parent [Annesi et al 2003;Fukuma et al 2004;Gennaro et al 2003;Kimura et al 2005;Nabbout et al 2003], suggesting the possiblity of reduced penetrance. The reason why the transmitting parent was less affected is unknown.…”

Section: Introductionmentioning

confidence: 99%

Parental mosaicism can cause recurrent transmission ofSCN1A mutations associated with severe myoclonic epilepsy of infancy

et al. 2006

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De novo mutations in the SCN1A gene, encoding the alpha1-subunit of the neuronal voltagegated sodium channel Nav1.1, are the most frequent genetic cause of Severe Myoclonic Epilepsy of Infancy known so far. A few mutations inherited from an asymptomatic or mildly affected parent have been reported, suggesting that expression of the mutated gene may be variable in the transmitting parent. In this study, we report two unrelated families in which two children of unaffected parents had deleterious SCN1A mutations, and show evidence of somatic and germline mosaicism in the transmitting parents. In one of these families, direct sequencing of blood cell DNA was not sufficient to the SCN1A mutation in the transmitting asymptomatic parent who was mosaic for the mutation. We therefore developed a real-time PCR assay to selectively amplify and quantify the mutant allele present at low levels in the transmitting parent in both families. The allele-specific PCR technique used in this study will be of use in detecting other such cases. These findings will have major consequences for the genetic counseling of asymptomatic parents with only one affected child.

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Epilepsy: Genetics

Everett¹

2010

Encyclopedia of Life Sciences

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At least 40% of all epilepsies have a genetic basis. Some forms of epilepsy have a simple Mendelian mode of inheritance, but these are very rare. The more common forms have a complex genetic background potentially involving several genes. Traditional methodologies for finding disease genes have been relatively successful for Mendelian forms of epilepsy. Although these approaches have been less successful for the common, complex epilepsies, it has still been possible to identify some disease‐associated genes. Most of the genes involved in epilepsy encode ion channel subunits making epilepsy an example of a ‘channelopathy’. The introduction of next generation genetic technologies has increased hope of identifying the specific genetic variants which contribute to individual susceptibility to common and Mendelian epilepsy; and with this comes hope of new deoxyribonucleic acid (DNA)‐based diagnostic techniques and the development of more specific therapies. Key Concepts: A large proportion of epilepsies have a genetic basis. The majority of genetic epilepsies demonstrate a complex mode of inheritance. Complex inheritance indicates that disease is caused by a combination of genetic changes potentially combined with nongenetic factors. Mode of inheritance can vary between families. Epilepsy is primarily a channelopathy; a disease caused by dysfunction of ion channels. Some genetic changes directly cause disease whereas others alter disease susceptibility. Genetic changes in the same gene can result in different epilepsies. New genetic technologies will facilitate the identification of genetic changes causing both Mendelian and complex epilepsy.

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Two Novel SCN1A Missense Mutations in Generalized Epilepsy with Febrile Seizures Plus

Cited by 51 publications

References 6 publications

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

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

Parental mosaicism can cause recurrent transmission ofSCN1A mutations associated with severe myoclonic epilepsy of infancy

Epilepsy: Genetics

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Two Novel SCN1A Missense Mutations in Generalized Epilepsy with Febrile Seizures Plus

Cited by 51 publications

References 6 publications

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

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

Parental mosaicism can cause recurrent transmission ofSCN1A mutations associated with severe myoclonic epilepsy of infancy

Epilepsy: Genetics

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

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