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.

Public Health Relevance

Neuronal communication is dependent upon the generation of action potentials by voltage-gated sodium channels. The sodium channel SCN8A (Nav1.6), first described by our laboratory in 1995, is one of the major channels involved in neuronal activity in the brain. Mutations of SCN8A cause neurological disorders such as ataxia, dystonia, tremor, and cognitive deficits. The goals of our work are to identify new mutations of SCN8A and related channels in patients with neurological and psychiatric disease, and to understand the functional effects of each mutation. We are studying mutations that affect interactions of the sodium channels with other proteins, and mutations that alter behavior and cognition. We are using mouse models to identify the subsets of neurons responsible for anxiety-like behavior resulting from reduced expression of Nav1.6. We will evaluate the role of Nav1.6 in human disease by functional analysis of variants identified in our laboratory and also by analysis of variants identified in large scale genome sequencing projects. Our specialized reagents and mutant mouse lines enable us to contribute to the functional genomics of SCN8A and its role in human disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Silberberg, Shai D
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Estacion, Mark; O'Brien, Janelle E; Conravey, Allison et al. (2014) A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis 69:117-23
Jones, Julie M; Meisler, Miriam H (2014) Modeling human epilepsy by TALEN targeting of mouse sodium channel Scn8a. Genesis 52:141-8
de Kovel, Carolien G F; Meisler, Miriam H; Brilstra, Eva H et al. (2014) Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res 108:1511-8
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