Mutation of poly(A) RNA binding protein, ZC3H14, leads to Intellectual Disability

Poly(A) RNA 结合蛋白 ZC3H14 突变导致智力障碍

• 批准号: 8774236
• 负责人: Jennifer Rha
• 金额: $ 2.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774236
• 关键词: Actins; Address; Affect; Animal Model; Axon; Binding; Biological Assay; Brain; Cell Line; Cell Nucleus; Cells; Complement; Complex; Coupled; Cytoplasm; Cytoplasmic Granules; Data; Defect; Dendrites; Development; Disease; Drosophila genus; Functional disorder; Gene Expression; Genetic Code; Goals; Hemocytes; Hereditary Disease; Hippocampus (Brain); Housing; Image; Immunoblotting; Immunofluorescence Immunologic; Immunoprecipitation; Intellectual functioning disability; Laboratories; Length; Life; Link; Messenger RNA; Microarray Analysis; Microscopy; Molecular; Movement; Mus; Mutate; Mutation; Neuronal Dysfunction; Neurons; Orthologous Gene; Other Genetics; Patients; Peptide Initiation Factors; Poly(A) Tail; Poly(A)+ RNA; Polyadenylation; Population; Post-Transcriptional Regulation; Process; Proteins; Quality of life; RNA; RNA-Binding Proteins; Ribosomes; Role; Site; Small Interfering RNA; Testing; Transcript; Translations; Zinc Fingers; base; developmental disease; genome-wide; improved; insight; mRNA Expression; novel; polyadenosine; polyadenylated messenger RNA; prevent; trafficking

DESCRIPTION (provided by applicant): Intellectual disability (ID) is the most common developmental disorder in the US. Patients with ID suffer from significantly subaverage intellectual function (IQ d70), which impinges on quality of life. In a collaborative effort, our laboratory has recently discovered novel mutations causative for autosomal recessive ID (ARID). These mutations are found in ZC3H14, a zinc finger polyadenosine RNA binding protein. This finding uncovers the molecular basis for disease in these patients and provides strong evidence that ZC3H14 is essential for proper brain function. Functional characterization of ZC3H14 is crucial for understanding both normal brain function and the molecular mechanism underlying ARID in these patients. Studies of ZC3H14 orthologs in model organisms provide insight into the role of this protein in post-transcriptional regulation of gene expression and key evidence for a critical role in neurons. We plan to exploit mouse neuronal cell lines to address our hypothesis that ZC3H14 is required for proper expression of specific mRNA targets that are critical for neuronal function. For our first aim, we will validate candidate ZC3H14 targets and use a discovery-based approach to search for novel targets of ZC3H14. In our second aim, we will both examine poly(A) tail length of specific transcripts and use state-of-the-art microscopy to determine whether ZC3H14 is required for proper localization of target mRNAs. By understanding how ZC3H14 controls expression of important target mRNAs, we can begin to address molecular mechanisms critical for normal brain function. Our long-term goal is to understand how dysregulation of post-transcriptional control of mRNA in neurons leads to neuronal dysfunction and consequently impaired brain function.

描述(申请人提供)：智力障碍(ID)是美国最常见的发育障碍。ID患者的智力功能明显低于平均水平(智商D70)，影响生活质量。在一项合作努力中，我们的实验室最近发现了导致常染色体隐性遗传ID(ARID)的新突变。这些突变在ZC3H14中发现，ZC3H14是一种锌指多腺苷RNA结合蛋白。这一发现揭示了这些患者疾病的分子基础，并提供了强有力的证据，表明ZC3H14对于正常的大脑功能是必不可少的。ZC3H14的功能特征对于了解这些患者的正常脑功能和导致AND的分子机制至关重要。在模式生物中对ZC3H14同源物的研究为深入了解该蛋白在基因表达的转录后调控中的作用提供了关键证据，并证明了该蛋白在神经元中的关键作用。我们计划利用小鼠神经细胞系来解决我们的假设，即ZC3H14是正确表达对神经元功能至关重要的特定信使核糖核酸靶标所必需的。对于我们的第一个目标，我们将验证候选的ZC3H14目标，并使用基于发现的方法来搜索ZC3H14的新目标。在我们的第二个目标中，我们将检查特定转录本的Poly(A)尾长，并使用最先进的显微镜来确定是否需要ZC3H14来正确定位目标mRNAs。通过了解ZC3H14是如何控制重要靶标mRNAs的表达，我们可以开始解决对正常大脑功能至关重要的分子机制。我们的长期目标是了解神经元中转录后控制基因的失调如何导致神经元功能障碍，从而损害大脑功能。