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Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B
R H Wallace1, D W Wang, R Singh
1Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide, SA, Australia.
Insights
Researchers identified a SCN1B gene mutation causing a loss-of-function in voltage-gated sodium channels, linking it to generalized epilepsy with febrile seizures plus (GEFS+). This discovery advances understanding of epilepsy as a channelopathy.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Febrile seizures are common in young children, with a small percentage developing epilepsy.
- Generalized epilepsy with febrile seizures plus (GEFS+) is a specific epilepsy syndrome with complex inheritance patterns.
- Previous research mapped two loci (FEB1, FEB2) for febrile seizures, but causative genes remained elusive.
Purpose of the Study:
- To identify the genetic cause of GEFS+ in a large family.
- To investigate the functional impact of identified mutations on sodium channel function.
Main Methods:
- Linkage analysis to identify the chromosomal region associated with GEFS+.
- Mutation screening of candidate genes within the linked region, specifically focusing on SCN1B.
- Functional studies using Xenopus laevis oocyte co-expression to assess the impact of the mutation on channel activity.
Main Results:
- Linkage was established to chromosome region 19q13.1 in the GEFS+ family.
- A novel mutation in the SCN1B gene, encoding the voltage-gated sodium channel beta1 subunit, was identified.
- Functional studies confirmed that the SCN1B mutation leads to a loss-of-function by disrupting channel-gating kinetics.
Conclusions:
- The SCN1B gene mutation is causative for GEFS+ in this family, highlighting its role in epilepsy pathogenesis.
- This finding supports the concept of idiopathic epilepsies as channelopathies.
- Further investigation into other sodium channel subunit genes is warranted for complex inherited epilepsies and febrile seizures.
Abstract:
Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.