A Neurogenomics Approach to Study the Contribution of AUTS2 to Autism

Background:  Autism susceptibility candidate 2 (AUTS2) was first identified as a possible risk gene for autism in a study of a monozygotic twin pair concordant for autism with a balanced translocation in the gene. Since then, translocations and copy number variations in AUTS2 have been identified in multiple individuals with autism and other neurodevelopmental phenotypes, including intellectual disability, seizures, short stature, cerebral atrophy and microcephaly. While it is one of the largest genes in the human genome, spanning over 1.2 Mb on chromosome 7q11.2, its function is yet unknown.

Objectives:  The aim of this study was to uncover critical pathways involved in autism by investigating the molecular functions of AUTS2 and the effects of AUTS2 haploinsufficiency.

Methods: We studied the cellular localization and interactome of AUTS2, as well as the effects of perturbing the expression of this gene on global gene expression and neuronal differentiation. We performed a yeast two-hybrid assay and co-immunoprecipitation to identify proteins interacting with AUTS2. In vitro corticogenesis was used to study the effects of AUTS2 knockdown. We used expression microarrays to profile the transcriptome of knockdown cells during neuronal differentiation.

Results: We found that AUTS2 is a nuclear protein that is induced during the first stages of neuronal differentiation. Knockdown of AUTS2 during neuronal differentiation caused an increase in cell death and apoptosis. We also found that AUTS2 interacts with a polycomb group protein, explaining the changes in histone marks and the upregulation of polycomb target genes in heterozygous knockout cells. The regulatory network of AUTS2 was enriched for common variants that increase the risk of autism.  

Conclusions:  Our results suggest that AUTS2 is involved in transcriptional control during neuronal differentiation as a part of a polycomb complex. Knockdown of AUTS2 increase cell death during neuronal differentiation and could explain the microcephaly and cerebral atrophy phenotypes observed in individuals with mutations in AUTS2. The findings also suggest that AUTS2 regulates other genes that may function as risk genes for autism. As such, AUTS2 can provide a valuable entry-point to the understanding of neural pathways relevant to autism and other neurodevelopmental disorders.