| Voltage-gated sodium channels (VGSCs) play a role in the generation of action potentials in excitable cells, including neurons. VGSCs contain one pore-forming alpha subunit, one non-covalently linked (beta1 or beta3) and one covalently linked beta subunit (beta2 or beta4). VGSC beta subunits participate in channel modulation and cell adhesion. SCN1B, the gene encoding beta1, is expressed as two splice variants: beta1 and beta1B. Both splice variants share a signal peptide and extracellular immunoglobulin loop domain in their N-termini. In contrast, the C-termini of each protein have little to no conservation. beta1 contains a transmembrane domain, while beta1B does not. Our results show that beta1B is a secreted cell adhesion molecule that promotes neurite outgrowth. beta1B is the predominantly expressed SCN1B splice variant during fetal brain development. We predict that beta1B plays important roles in the establishment of neuronal excitability and disruptions in its expression may lead to brain disease.;Heterozygous mutations in SCN1B have been reported as a cause of mild to moderate forms of Genetic Epilepsy with Febrile Seizures Plus (GEFS+). Here we report the first case of the epileptic encephalopathy Dravet Syndrome, characterized at the severe end of the GEFS+ spectrum, associated with a homozygous mutation of SCN1B. Our work demonstrates that the protein generated by this mutation, p.R125C, is trafficking deficient, resulting in the functional null phenotype in homozygous probands. Consistent with this, we propose that Scn1b null mice are an animal model of Dravet Syndrome.;To date, all reported SCN1B mutations associated with epilepsy are located in the region common to beta1 and beta1B. Here we describe the first SCN1B mutation in the region exclusive to beta1B associated with primary generalized epilepsy in heterozygous state. The protein produced by the mutation, p.G257R, is trafficking deficient, similar to p.R125C. Not surprisingly, its ability to promote neurite outgrowth in vitro is abolished. These results support our hypothesis that beta1B plays a role in axon guidance during fetal development of the CNS. Taken together, this thesis work makes significant and novel contributions to our understanding of the role of VGSC SCN1B in normal brain development and neurological disease. |
