Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The <span style="font-style:italic;">Aristaless-</span>related homeobox <span style="font-style:italic;">(ARX)</span> gene encodes a paired-type homeodomain transcription factor with critical roles in embryonic development. Mutations in <span style="font-style:italic;">ARX</span> give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. To capture the genetics and molecular disruptions that underpin the <span style="font-style:italic;">ARX</span>-associated clinical phenotypes, we undertook a transcriptome wide RNASeq approach to analyse developing (12.5 dpc) telencephalon of mice modelling two recurrent polyalanine expansion mutations with different phenotypic severities in the <span style="font-style:italic;">ARX</span> gene. Here we report 238 genes significantly deregulated (Log2FC  > +/−1.1, <span style="font-style:italic;">P</span>-value <0.05) when both mutations are compared to wild-type (WT) animals. When each mutation is considered separately, a greater number of genes were deregulated in the severe PA1 mice (825) than in the PA2 animals (78). Analysing genes deregulated in either or both mutant strains, we identified 12% as implicated in ID, epilepsy and autism (99/858), with ∼5% of them as putative or known direct targets of ARX transcriptional regulation. We propose a core pathway of transcription regulators, including <span style="font-style:italic;">Hdac4</span>, involved in chromatin condensation and transcriptional repression, and one of its targets, the transcription factor <span style="font-style:italic;">Twist1</span>, as potential drivers of the ID and infantile spasms in patients with <span style="font-style:italic;">ARX</span> polyalanine expansion mutations. We predict that the subsequent disturbance to this pathway is a consequence of ARX protein reduction with a broader and more significant level of disruption in the PA1 in comparison to the PA2 mice. Identifying early triggers of <span style="font-style:italic;">ARX</span>-associated phenotypes contributes to our understanding of particular clusters/pathways underpinning comorbid phenotypes that are shared by many neurodevelopmental disorders.</span>

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