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Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B

Abstract

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder1. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures2. Segregation analysis suggests the majority of cases have complex inheritance3 but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified4,5. 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 seizures6. 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 ß1 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 ß1 subunit with a brain Na+-channel ß 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.

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Figure 1: Chromosome 19 haplotypes for the portion of the GEFS+ pedigree for which DNA was available.
Figure 2: Graph of multipoint lod scores based on genetic markers from chromosme 19q.
Figure 3: Identification of a mutation in SCN1B.
Figure 4
Figure 5: Functional characterization of SCN1B mutant.

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Acknowledgements

This work was supported by the Women's and Children's Hospital Foundation, the National Health and Medical Research Council of Australia, the Austin Hospital Medical Research Foundation, Royal Children's Hospital Medical Research Foundation, NIH grant NS32387 to A.L.G., a grant in aid from the German Ministry of Research (BMBF), and an International Research Scholars award from the Howard Hughes Medical Institute to G.R.S. We thank M. Seeger, J. Spence, M. Lake and K. Crossland for technical assistance, J. Gecz for technical advice and the family members for participation.

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Correspondence to John C. Mulley.

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Wallace, R., Wang, D., Singh, R. et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B. Nat Genet 19, 366–370 (1998). https://doi.org/10.1038/1252

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