Sodium channel SCN1A and epilepsy: Mutations and mechanisms
Top Cited Papers
Open Access
- 2 September 2010
- Vol. 51 (9), 1650-1658
- https://doi.org/10.1111/j.1528-1167.2010.02640.x
Abstract
Mutations in a number of genes encoding voltage‐gated sodium channels cause a variety of epilepsy syndromes in humans, including genetic (generalized) epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS, severe myoclonic epilepsy of infancy). Most of these mutations are in the SCN1A gene, and all are dominantly inherited. Most of the mutations that cause DS result in loss of function, whereas all of the known mutations that cause GEFS+ are missense, presumably altering channel activity. Family members with the same GEFS+ mutation often display a wide range of seizure types and severities, and at least part of this variability likely results from variation in other genes. Many different biophysical effects of SCN1A‐GEFS+ mutations have been observed in heterologous expression systems, consistent with both gain and loss of channel activity. However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCN1A mutations.Keywords
This publication has 99 references indexed in Scilit:
- Genetic testing in the epilepsies—Report of the ILAE Genetics CommissionEpilepsia, 2010
- Altered Function of the SCN1A Voltage-gated Sodium Channel Leads to γ-Aminobutyric Acid-ergic (GABAergic) Interneuron AbnormalitiesJournal of Biological Chemistry, 2010
- Making sense of nonsense GABAA receptor mutations associated with genetic epilepsiesTrends in Molecular Medicine, 2009
- De novo mutations of voltage-gated sodium channel α II gene SCN2A in intractable epilepsiesNeurology, 2009
- A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet SyndromePLoS Genetics, 2009
- A Functional Null Mutation ofSCN1Bin a Patient with Dravet SyndromeJournal of Neuroscience, 2009
- A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutationNeurobiology of Disease, 2009
- Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancyProceedings of the National Academy of Sciences, 2009
- Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsyNeuroscience Letters, 2008
- A single sodium channel mutation produces hyper- or hypoexcitability in different types of neuronsProceedings of the National Academy of Sciences, 2006