Cellular and molecular mechanisms underlying DDX3X syndrome

DDX3X 综合征的细胞和分子机制

基本信息

批准号：
10320963
负责人：
Stephen Nicholas Floor
金额：
$ 66.28万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10320963
关键词：
Acute Address Alleles Antisense Oligonucleotides Axon Biochemical Biology Brain Cell Cycle Cell Fate Control Cell Line Cell physiology Cells Clinical Collaborations Communities Data Databases Development Developmental Delay Disorders Diagnostic Disease Electroporation Embryo Etiology Event Family Female Generations Genes Human Image Impairment Individual Intellectual functioning disability Link Measures Messenger RNA Metabolism Microcephaly Missense Mutation Molecular Molecular Chaperones Mus Mutation Neurodevelopmental Disorder Neurons Nonsense Mutation Nuclear Pore Complex Pathology Phenotype Population Protein Biosynthesis RNA RNA Helicase RNA-Binding Proteins Research Role Severities Structure Syndrome Testing Therapeutic Therapeutic Intervention Transcript Translating Translational Regulation Translations Variant autism spectrum disorder brain malformation cell fate specification genetic variant helicase human model impaired brain development in utero in vivo induced pluripotent stem cell insight loss of function loss of function mutation mouse model mutant mutation carrier nerve stem cell nervous system disorder neurogenesis nucleotide analog postnatal progenitor relating to nervous system ribosome profiling stem cells transcriptome virtual

项目摘要

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.

抽象的 DDX3X中的突变与自闭症谱系障碍（ASD）密切相关，并且可能在女性中占无法解释的发育延迟（DD）的1-3％神经发育障碍最常见。 DDX3X被认为是高信任的ASD Sfari基因的基因。 DDX3X编码死盒解旋酶家族的RNA结合蛋白。虽然与mRNA代谢有广泛的影响，但DDX3X最好以一种翻译为特征监管机构。尽管DDX3X和ASD之间存在牢固的联系，但实际上对 DDX3X在发育大脑中的功能或DDX3X突变扰动的机制细胞功能。此外，DDX3X如何影响神经祖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状况和治疗干预的潜力。我们的提议解决通过研究DDX3X突变如何损害脑发育和蛋白质，这些差距如何合成。我们的初步数据表明在神经祖细胞中对DDX3X的要求，表明翻译调节可能与疾病有关。这导致了我们的中心 DDX3X突变通过破坏祖细胞周期和关键目标的翻译。为了解决这一假设，我们将：定义DDX3X功能的损失损害小鼠模型中的细胞命运规范，确定DDX3X错义突变如何损害人类神经祖细胞功能和分化，并通过 DDX3X中哪些遗传变异改变了蛋白质的合成。我们多样化的科学方法使对DDX3X功能和发育作用的多方面理解。完成后这项研究将获得对DDX3X生物学的基本见解，并指导一个框架治疗干预。