Characterization of SCN2A Haploinsufficiency in Early Neurodevelopment Using Transcriptomic Analyses and Systems Biology

Oral Presentation
Saturday, May 12, 2018: 2:21 PM
Willem Burger Hal (de Doelen ICC Rotterdam)
J. Y. An1, S. Fazel Darbandi1, D. M. Werling2, G. B. Schwartz1, C. M. Keeshen3, K. J. Bender4 and S. Sanders1, (1)Psychiatry, University of California San Francisco, San Francisco, CA, (2)Psychiatry, UCSF, San Francisco, CA, (3)UCSF, San Francisco, CA, (4)Department of Neurology, UCSF, San Francicso, CA
Background: SCN2A is a voltage-gated sodium channel gene that encodes neuronal sodium channel NaV1.2 and plays a critical role in early neurodevelopment and action potential initiation. Large-scale genomic studies have demonstrated that SCN2A is associated with autism spectrum disorder (ASD), developmental delay, and seizures. Integrative analysis using electrophysiology and cellular data showed that ASD mutations impaired neuronal excitability in the developing brain (NaV1.2 loss-of-function).

Objectives: To understand the functional consequence of SCN2A loss-of-function mutation during the neurodevelopment, and whether transcriptional changes in SCN2A haploinsufficiency converge on biological pathways related to ASD neurobiology, suggesting that biological findings may be relevant to ASD in general.

Methods: From a heterozygous SCN2A deletion mouse model (Scn2a1wt/-), we collected samples from two developmental stages (postnatal day 7 (P7) and P30), equivalent to infancy and early adulthood in humans, and two brain regions (cortex and cerebellum). RNA-seq was performed on two biological replicates of these samples using a 50bp paired-end library. After adjusting for covariates, we identified differentially expressed genes in SCN2A deletion compared with wild-type littermates (SCN2A-DEX, ±1.5-fold change in expression; p-values ≤0.05 after Benjamini-Hochberg correction).

Results: We found distinct spatiotemporal gene expression changes in Scn2a1wt/- mice, largely for genes related to neuronal functions. Specifically, we found that SCN2A-DEX genes in the developing (P7) cortex are enriched for co-expression modules of synaptic genes in the ASD human postmortem cortex (Parikshak et al. 2016), as well as FMRP binding targets (Darnell et al. 2011). In addition, gene set enrichment analysis using cell type-specific expression profiles (Xu et al. 2014) showed that SCN2A-DEX genes are enriched in cortical projection neurons, particularly in layer 5 and 6 pyramidal neurons. This is consistent with our previous observation that SCN2A variants associated with ASD impair neuronal excitability in the developing pyramidal cell model (Willsey et al. 2013).

Conclusions: Our analysis of RNA-Seq data in this mouse model shows that SCN2A disruption in the developing cortex impacts numerous genes that have been highlighted in ASD pathology, suggesting that SCN2A and other causes of ASD may converge on common pathological pathways. Further characterization of SCN2A function may therefore provide an important window into the neurobiology of ASD.

See more of: Genetics
See more of: Genetics