The SCN8A gene encodes the voltage-gated sodium channel Nav1.6 that is expressed in neurons throughout the central and peripheral nervous system. Nav1.6 is concentrated at the axon initial segment and nodes of Ranvier. Mutations of SCN8A affect many aspects of brain and peripheral nerve function. In 2012 we described the first mutation of SCN8A in a child with early onset epileptic encephalopathy. Since then more than 150 de novo missense mutations have been identified in this severe form of epilepsy (OMIM # 614558). Our functional characterization of 10 patient mutations demonstrated that gain-of-function mutations resulting in channel hyperactivity are the major pathogenic mechanism underlying SCN8A encephalopathy. We generated a mouse model of the first identified SCN8A mutation, p.Asn1768Asp, that is widely used for evaluation of therapeutic interventions. We will use this model to isolate a recently discovered genetic modifier that results in complete rescue of seizures and sudden death. We will also assess the pre-clinical effectiveness of antisense oligonucleotides and RNAi reagents that suppress the expression of the dominant SCN8A mutation in the N1768D mouse model. To explore the basis for the severe hypotonia associated with many SCN8A mutations, we have generated a new conditional mouse model with CRE-dependent expression of the more severe patient mutation p.Arg1872Trp. We will use this new model to examine the role of mutant Nav1.6 in specific subsets of neurons at varying stages of development. This conditional model will also be used to directly test the contribution of cardiac expression of hyperactive Nav1.6 to the risk of sudden death. These studies will provide new knowledge regarding pathogenic mechanisms underlying SCN8A encephalopathy, and will test the effectiveness of gene suppression as a therapeutic intervention for this severe neurological disorder.
Mutations in neuronal ion channels result in neurological and psychiatric disorders including epileptic encephalopathy. Our mouse models reveal underlying pathogenic mechanisms and permit pre-clinical testing of therapeutic interventions. We will identify a genetic modifier that may provide a novel therapeutic target for patients with SCN8A encephalopathy.
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