Animal Models for SCN2A Neurodevelopmental Disorders

Project: Research project

Description

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 may include genetic modifiers. Consistent with this, the epilepsy phenotype of Scn2aQ54 mice was strongly influenced by genetic background. To address the effect of genomic background variation, we will cross Scn2a mutant mice with several strains and survey neurodevelopmental and epilepsy phenotypes in F1 offspring (Aim 2). We will focus on a subset of parental strains of the collaborative cross and diversity outbred genetic mapping resources to support future leveraging of these resources. The proposed Scn2a strains and phenotype information will be deposited in the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC) and Mouse Genome Database (MGD/MGI). This proposal will deliver two novel mouse models of NDD with Scn2a driver mutations and make them readily available to the wider research community to enable independent studies of Scn2a channel variants in their native context at the cellular, circuit, systems and whole animal levels, as well as enable studies of gene-gene and gene-environment interactions. This will advance our understanding of the pathophysiology of brain development disorders and may ultimately lead to the development of novel therapies.
StatusActive
Effective start/end date8/1/187/31/20

Funding

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

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Animal Models
Epilepsy
Phenotype
Intellectual Disability
Brain Diseases
NAV1.2 Voltage-Gated Sodium Channel
Mutation
Genome
Neurodevelopmental Disorders
Infantile Spasms
Gene Transfer Techniques
Gene-Environment Interaction
Phosphopyruvate Hydratase
Transgenes
Genes
Schizophrenia
Complementary DNA
Databases
Brain
Research