Functional Genetics of the Neuronal Sodium Channel Gene SCN8A

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DESCRIPTION (provided by applicant): The voltage-gated sodium channel SCN8A encoding Nav1.6 is expressed in neurons throughout the central and peripheral nervous system, and is concentrated at axonal initial segments and nodes of Ranvier. Because of its widespread expression, mutations of SCN8A affect many aspects of brain and peripheral nerve function. This proposal is focused on identifying new mutations of human SCN8A and related sodium channels in patients, and carrying out functional analysis using in vitro and in vivo expression systems to evaluate the pathogenicity of the mutations. We have established a pipeline for functional characterization of sodium channel mutations identified by whole exome sequencing projects in patients with neurological and psychiatric disorders. Seven novel human mutations were identified and characterized during the previous funding period. A de novo SCN8A mutation in a patient with epileptic encephalopathy, features of autism, and SUDEP causes elevated persistent current leading to neuronal hyperexcitability. We will generate a mouse model of this disorder, to elucidate the effects on neuronal and cardiac function. Haploinsufficiency of SCN8A in results in intellectual disability and anxiety-like behavior. We wil cross our floxed Scn8a mouse with SERT-CRE and VIAAT-CRE mice to probe the contributions of serotonergic neurons and inhibitory interneurons to the abnormal behaviors. We will carry out in vivo biotinylation of an Avi-Tagged Nav1.6 transgene by the BirA biotin ligase transgene in an unbiased search for proteins that interact with Nav1.6. We will determine whether interaction with MAP1B mediates vesicular transport of Nav1.6 to the nodes of Ranvier. These studies will contribute to understanding basic function and clinical consequences of mutations in Nav1.6, a major determinant of neuronal activity.