Cellular and molecular mechanisms underlying DDX3X syndrome

摘要 DDX 3X的突变与自闭症谱系障碍（ASD）密切相关，并且可能 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DDX 3X被视为高置信度ASD SFARI基因。DDX 3X编码DEAD盒解旋酶家族的RNA结合蛋白。 虽然广泛涉及mRNA代谢，但DDX 3X最好被表征为翻译蛋白。 调节器尽管DDX 3X和ASD之间存在强大的联系，但实际上对 DDX 3X在发育中的大脑中的功能，也不是DDX 3X突变干扰的机制 细胞功能此外，DDX 3X如何影响神经祖细胞以及 如何控制目标的平移这限制了我们对ASD原因的理解， 这种常见的情况和治疗干预的潜力。我们的建议涉及 通过研究DDX 3X突变如何损害大脑发育和蛋白质来弥补这些差距 合成.我们的初步数据表明，神经祖细胞中需要DDX 3X， 这表明翻译调控可能与疾病有关。这导致了我们的中央 假设DDX 3X突变通过破坏祖细胞周期损害神经发生， 关键目标的翻译为了解决这一假设，我们将：定义DDX 3X功能丧失如何 在小鼠模型中损害细胞命运特化，确定DDX 3X错义突变如何 损害人类神经祖细胞功能和分化，并通过以下方式鉴定机制： DDX 3X中的遗传变异改变了蛋白质合成。我们多样化的科学方法使 这是对DDX 3X功能和发育作用的多方面理解。完成后 这项研究将获得DDX 3X生物学的基本见解，并指导框架， 治疗干预

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.