title: Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.
abstract: Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear.
  
  
  
  We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express NaV1.2.
  
  
  
  In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability.
  
  
  
  This functional characterization thus identifies SCN2A mutation and NaV1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.
authors.affiliation: Center for Integrative Neuroscience, Kavli Institute for Fundamental Neuroscience, Department of Neurology, San Francisco, San Francisco; Computational Research Division , Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Roy
authors.initials: R
authors.lastname: Ben-Shalom
authors.affiliation: Center for Integrative Neuroscience, Kavli Institute for Fundamental Neuroscience, Department of Neurology, San Francisco, San Francisco.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Keeshen
authors.affiliation: Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico.
authors.forename: Kiara N
authors.initials: KN
authors.lastname: Berrios
authors.affiliation: Department of Psychiatry, San Francisco, San Francisco; UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.
authors.forename: Joon Y
authors.initials: JY
authors.lastname: An
authors.affiliation: Department of Psychiatry, San Francisco, San Francisco; UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Center for Integrative Neuroscience, Kavli Institute for Fundamental Neuroscience, Department of Neurology, San Francisco, San Francisco; UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco; Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico. Electronic address: kevin.bender@ucsf.edu.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Bender
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003198:Computer Simulation; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008564:Membrane Potentials / Q000502:physiology; D008959:Models, Neurological; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000378:metabolism; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human
keywords: Autism spectrum disorder; Epilepsy; Na(V)1.2; SCN2A; Seizure; electrophysiology