Cellular and molecular mechanisms underlying DDX3X syndrome

摘要 DDX3X基因突变与自闭症谱系障碍(ASD)密切相关，并可能 占女性不明原因发育迟缓(DD)的1-3%，使其成为 最常见的神经发育障碍。DDX3X被认为是一款高可靠的ASD SFARI基因。DDX3X编码DEAD-box解旋酶家族的RNA结合蛋白。 虽然DDX3X广泛参与mRNA代谢，但最好将其描述为一种翻译的 调整器。尽管DDX3X和ASD之间存在强大的联系，但人们几乎对此一无所知 DDX3X在发育中大脑中的作用以及DDX3X突变扰乱的机制 细胞功能。此外，DDX3X如何影响神经前体细胞和 它如何控制目标的翻译。这限制了我们对ASD原因的理解 这种常见的情况和治疗干预的可能性。我们的建议解决了 这些差距是通过研究DDX3X突变如何损害大脑发育和蛋白质来实现的 综合。我们的初步数据表明神经前体细胞对DDX3X的需求 这表明翻译调控可能与疾病相关。这导致了我们的中央 假设DDX3X突变通过扰乱祖细胞周期而损害神经发生 关键目标的翻译。为了解决这一假设，我们将：定义DDX3X如何丧失功能 在小鼠模型中损害细胞命运规范，确定DDX3X错义突变 损害人类神经前体功能和分化，并确定其机制(S) DDX3X中的哪些遗传变异会改变蛋白质的合成。我们多样化的科学方法使 这是对DDX3X功能和发育作用的多方面理解。在完成后 在这项研究中，我们将获得对DDX3X生物学的基本见解，并指导 治疗性干预。

Abstract Mutations in DDX3X are strongly associated with autism spectrum disorder (ASD), and may account for 1-3% of unexplained developmental delay (DD) in females, making this one of the most common of neurodevelopmental disorders. DDX3X is considered a high confidence ASD gene by SFARI gene. DDX3X encodes an RNA-binding protein of the DEAD-box helicase family. While broadly implicated in mRNA metabolism, DDX3X is best characterized as a translational regulator. Despite the robust link between DDX3X and ASD, virtually nothing is known about DDX3X function in the developing brain nor the mechanisms by which DDX3X mutations perturb cellular function. Further, it remains largely unknown how DDX3X impacts neural progenitors and how it controls translation of its targets. This limits our understanding of the causes of ASD for this common condition and the potential for therapeutic intervention. Our proposal addresses these gaps by investigating how DDX3X mutations impair brain development and protein synthesis. Our preliminary data indicates requirements for DDX3X in neural progenitors and suggests that translational regulation may be relevant for disease. This has led to our central hypothesis that DDX3X mutations impair neurogenesis by disrupting the progenitor cell cycle and translation of key targets. To address this hypothesis we will: Define how DDX3X loss of function impairs cell fate specification in mouse models, determine how DDX3X missense mutations impair human neural progenitor function and differentiation, and identify the mechanism(s) by which genetic variants in DDX3X alter protein synthesis. Our diverse scientific approaches enable this multifaceted understanding of DDX3X function and developmental role. Upon completion of this study we will gain fundamental insights into DDX3X biology and guide a framework for therapeutic intervention.