Animal Models for SCN2A Neurodevelopmental Disorders

Project: Research project

Project Details


Approximately 1 in 6 children in the United States are affected by neurodevelopmental disorders (NDD), which pose a significant burden to patients, families and society. Among NDD, autism spectrum disorder (ASD), intellectual disability (ID), developmental delay (DD) and early-onset epilepsy account for approximately 40% of cases. There is considerable evidence for a significant contribution of de novo genetic mutations to these disorders, and variants in SCN2A are a major genetic driver contributing to several NDD, including ASD, ID, DD, epileptic encephalopathies, and schizophrenia. This suggests proper function of Nav1.2 voltage-gated sodium channels, encoded by SCN2A, are important for normal brain development and function. Twenty-years ago, we developed the Scn2aQ54 mouse model that is hemizygous for a mutant Nav1.2 channel. Scn2aQ54 mice exhibit early-onset epilepsy and repetitive behaviors suggestive of autistic-like traits. Although this model exhibits some features of patients with SCN2A variants, it lacks construct validity. It was generated by random-insertion transgenesis of a mutated rat Scn2a cDNA under control of the neuron specific enolase (Eno2) promoter. Due to the nature of the transgene construct, the timing/location of expression may not faithfully recapitulate endogenous Scn2a and neonatal splicing events do not occur. In light of these limitations and transformative advances in genome engineering, we propose to make improved mouse models carrying human SCN2A variants, including an infantile spasms variant and a recurrent ASD/ID variant. We will generate two mouse lines using crispr/CAS9 and homology directed repair, and perform initial characterization of cellular, neurodevelopmental and epilepsy phenotypes on a C57BL/6J background (Aim 1). SCN2A variants are associated a wide-degree phenotype heterogeneity, even among individuals carrying the same mutation. This suggests that phenotype expressivity can be influenced by other factors, which ma
Effective start/end date8/1/181/31/22


  • Office of the Director, National Institutes of Health (5R21OD025330-02)


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