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A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

ABSTRACT: We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.

SUBMITTER: Escayg A

PROVIDER: S-EPMC1275640 | biostudies-literature | 2001 Apr

REPOSITORIES: biostudies-literature

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A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

Escayg A A Heils A A MacDonald B T BT Haug K K Sander T T Meisler M H MH

American journal of human genetics 20010314 4

We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multip ...[more]

PMID: 11254445

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Project description:Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations.Using immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleep-wake pattern following 6 h of sleep deprivation.Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation.These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations.

Dataset Information

A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

Publications

A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

Similar Datasets

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