Whole-exome sequencing studies of sporadic autism cases have identified SCN2A, which encodes the neuronal voltage-gated sodium channel NaV1.2, as one of the most commonly mutated genes associated with autism. How dysfunctional NaV1.2 affects neurons and consequent circuit function to produce behaviors associated with autism is not well understood.

Geoffrey Pitt and his colleagues at Duke University have recently characterized a familial autism mutation (R1902C) in SCN2A at the structural and biophysical level. This detailed understanding provides a platform upon which to generate a mouse knock-in model, offering a powerful tool for the research community to examine effects at any level — from the atomic (structural) level to behavioral phenotypes — of a monogenic autism mutation.

The researchers propose to generate a mouse bearing the R1902C knock-in mutation within SCN2A (using CRISPR/CAS9 technology) and to characterize the initial physiological and behavioral phenotypes. This mouse model, which will be shared with the research community after initial characterization, will then serve as a substrate for higher-level investigations into how a specific mutation in an autism susceptibility gene leads to the full spectrum of the disorder.