Cellular and circuit effects of SCN2A haploinsufficiency

  • Awarded: 2017
  • Award Type: Pilot
  • Award #: 513133

Mutations identified by exome sequencing demonstrate that disruption of the gene SCN2A, which encodes the neuronal sodium channel NaV1.2, is strongly associated with autism spectrum disorder (ASD). In fact, based on the combined data from sequencing the Simons Simplex Collection (SSC), the Autism Sequencing Consortium (ASC) and the recently published Autism Spectrum/Intellectual Disability Network, SCN2A shows the strongest evidence of association of any gene identified via exome sequencing. NaV1.2 channels are localized to the axon, and are important for action potential initiation, raising the possibility that mutations in SCN2A lead to ASD via alterations to axonal excitability. Given that the majority of ASD-associated genes have been linked to chromatin and synaptic regulation, understanding the distinct mechanism(s) by which SCN2A mutations lead to ASD offers potential novel insights into ASD biology.

Along with multiple de novo protein truncating variants, an excess of ASD-associated de novo missense mutations have been identified in SCN2A. Through a SFARI Explorer Award, Kevin Bender and colleagues have completed an electrophysiological screen of protein truncating and missense variants in the SSC and ASC cohorts1. Bender’s laboratory found that ASD-associated SCN2A missense mutations dampen or completely eliminate NaV1.2 ion flux, suggesting that many missense mutations share a common neurobiological phenotype that may be functionally similar to protein truncation.

Bender’s team now proposes to leverage in vitro and in vivo electrophysiology, 2-photon sodium and calcium imaging, and behavioral techniques to investigate how loss of NaV1.2 function affects brain development in mouse models. In doing so, Bender aims to elucidate how alterations in axonal excitability contribute to ASD.



1.Ben-Shalom R. et al. Biol. Psychiatry 82, 224-232 (2017) PubMed
Subscribe to our newsletter and receive SFARI funding announcements and news