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

描述（由申请人提供）：智力残疾（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（IQ 70），这影响了生活质量。在合作努力下，我们的实验室最近发现了常染色体隐性ID （ARID）的新突变。这些突变是在锌指聚腺苷RNA结合蛋白ZC3H14中发现的。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，证明ZC3H14对正常的脑功能至关重要。ZC3H14的功能表征对于了解这些患者的正常脑功能和干旱的分子机制至关重要。对模式生物中ZC3H14同源物的研究提供了该蛋白在转录后基因表达调控中的作用，并为其在神经元中的关键作用提供了关键证据。我们计划利用小鼠神经细胞系来解决我们的假设，即ZC3H14是特定mRNA靶点的适当表达所必需的，这些靶点对神经元功能至关重要。对于我们的第一个目标，我们将验证候选ZC3H14靶标，并使用基于发现的方法搜索ZC3H14的新靶标。在我们的第二个目标中，我们将检查特定转录本的poly(A)尾长度，并使用最先进的显微镜来确定ZC3H14是否需要正确定位目标mrna。通过了解ZC3H14如何控制重要靶mrna的表达，我们可以开始解决正常脑功能的关键分子机制。我们的长期目标是了解神经元中mRNA转录后控制的失调如何导致神经元功能障碍，从而损害脑功能。

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.