Mattiske Tessa, Lee Kristie, Gecz Jozef, Friocourt Gaelle, Shoubridge Cheryl
Department of Paediatrics, Adelaide Medical School.
Robinson Research Institute, University of Adelaide, SA, Australia.
Hum Mol Genet. 2016 Dec 15;25(24):5433-5443. doi: 10.1093/hmg/ddw360.
The Aristaless-related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in embryonic development. Mutations in ARX give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. To capture the genetics and molecular disruptions that underpin the ARX-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 ARX gene. Here we report 238 genes significantly deregulated (Log2FC > +/-1.1, P-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 Hdac4, involved in chromatin condensation and transcriptional repression, and one of its targets, the transcription factor Twist1, as potential drivers of the ID and infantile spasms in patients with ARX 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 ARX-associated phenotypes contributes to our understanding of particular clusters/pathways underpinning comorbid phenotypes that are shared by many neurodevelopmental disorders.
无尾相关同源框（ARX）基因编码一种配对型同源结构域转录因子，在胚胎发育中起关键作用。ARX基因突变会导致智力障碍（ID）、癫痫和脑畸形综合征。为了探究构成ARX相关临床表型基础的遗传学和分子破坏机制，我们采用转录组范围的RNA测序方法，分析了模拟ARX基因中两种具有不同表型严重程度的复发性聚丙氨酸扩展突变的小鼠发育中（胚胎第12.5天）的端脑。在此，我们报告，当将两种突变与野生型（WT）动物进行比较时，有238个基因显著失调（Log2FC＞/+/-1.1，P值＜0.05）。当分别考虑每种突变时，严重的PA1小鼠（825个）中失调的基因数量比PA2动物（78个）中更多。分析在任一或两种突变株中失调的基因，我们确定12%与ID、癫痫和自闭症有关（99/858），其中约5%是ARX转录调控的推定或已知直接靶点。我们提出了一个转录调节因子的核心途径，包括参与染色质浓缩和转录抑制的Hdac4，以及它的一个靶点转录因子Twist1，作为ARX聚丙氨酸扩展突变患者ID和婴儿痉挛的潜在驱动因素。我们预测，该途径随后的紊乱是ARX蛋白减少的结果，与PA2小鼠相比，PA1小鼠中这种紊乱的程度更广泛、更显著。确定ARX相关表型的早期触发因素有助于我们理解许多神经发育障碍共有的合并表型背后的特定簇/途径。
