SCN8A is an abundant voltage-gated sodium channel that is expressed throughout the mammalian brain, spinal cord and peripheral nervous system. During the previous funding period we identified mutations of SCN8A in the mouse that are responsible for ataxia, dystonia, and progressive paralysis, and mutations of SCN1A in patients with GEFS+ type 2. We propose to generate new genetic models that will contribute to understanding the normal expression and pathogenic potential of neuronal sodium channels. SCN8A is localized in the nodes of Ranvier in myelinated axons and in dendrites, and in presynapatic and postsynaptic membranes in the CNS. We will identify the protein domains responsible for subcellular localization by analysis of epitope-labeled chimeric channels in transgenic mice. We will investigate the transcriptional regulation of the SCN8A gene including identification of promoter(s) and enhancer elements. We will examine the regional distribution of alternative splicing in the brain and test a candidate site for RNA editing. Large scale genomic sequence of the SCN8A gene from human, mouse and puffer fish will be obtained and compared in order to identify evolutionarily conserved coding and noncoding sequences. We will generate mice with regulated conditional inactivation of SCN8A in specific neurons by targetting loxP sites into the SCN8A gene using homologous recombination. To produce models of human polygenic disease, we will cross SCN8A mutant mice with mice carrying null alleles of functionally related proteins such as SCN2A and the sodium channel beta subunits. This work will extend our knowledge of the physiological and cellular functions of SCN8A in the CNS and PNS and its role in neurological disease.
| Baker, Erin M; Thompson, Christopher H; Hawkins, Nicole A et al. (2018) The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. Epilepsia 59:1166-1176 |
| Wagnon, Jacy L; Mencacci, Niccolò E; Barker, Bryan S et al. (2018) Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat 39:965-969 |
| Chen, Chunling; Holth, Jerrah K; Bunton-Stasyshyn, Rosie et al. (2018) Mapt deletion fails to rescue premature lethality in two models of sodium channel epilepsy. Ann Clin Transl Neurol 5:982-987 |
| Ottolini, Matteo; Barker, Bryan S; Gaykema, Ronald P et al. (2017) Aberrant Sodium Channel Currents and Hyperexcitability of Medial Entorhinal Cortex Neurons in a Mouse Model of SCN8A Encephalopathy. J Neurosci 37:7643-7655 |
| Wagnon, Jacy L; Barker, Bryan S; Ottolini, Matteo et al. (2017) Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet 3:e170 |
| Lopez-Santiago, Luis F; Yuan, Yukun; Wagnon, Jacy L et al. (2017) Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy. Proc Natl Acad Sci U S A 114:2383-2388 |
| Sprissler, Ryan S; Wagnon, Jacy L; Bunton-Stasyshyn, Rosie K et al. (2017) Altered gene expression profile in a mouse model of SCN8A encephalopathy. Exp Neurol 288:134-141 |
| He, Fang; Jones, Julie M; Figueroa-Romero, Claudia et al. (2016) Screening for novel hexanucleotide repeat expansions at ALS- and FTD-associated loci. Neurol Genet 2:e71 |
| Malcolmson, Janet; Kleyner, Robert; Tegay, David et al. (2016) SCN8A mutation in a child presenting with seizures and developmental delays. Cold Spring Harb Mol Case Stud 2:a001073 |
| Barker, Bryan S; Ottolini, Matteo; Wagnon, Jacy L et al. (2016) The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin. Epilepsia 57:1458-66 |
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