Fragile X Spectrum as Model for Neurogenetic Mechanisms of Cognitive Dysfunction

脆性X在神经遗传学疾病中是独一无二的，因为它是唯一一种具有剂量反应的此类疾病 基于单基因的机制(CGG-重复-表型依赖)。此外，它还产生了不同的 与FMR1基因失调相关的不同致病机制的结果-低/缺失 脆性X综合征患者FMR1蛋白(FMRP)；“有毒”FMR1 RNA水平升高。由于这些原因， 特征，脆性X提供了一种独特的模型来开发一种“分子到头脑”的解释 神经遗传性疾病，然后可以用来产生关于疾病遗传基础的假说 分子机制不是很清楚。因此，该组件的总体目标是了解如何 单基因突变(FMR1)的变异导致两种疾病的一系列认知功能障碍 童年和成年。为此，我们将生成第一个详细的神经认知概况 一组整合的认知域，初步数据表明，这些认知域非常容易受到 FMRP的表达。该简介将由来自假设驱动的实验认知的数据组成 处理任务和磁共振成像(MRI)方法，将产生结构、功能和 互联互通措施。我们将这一特征称为FMR1敏感神经认知特征(FSNP)。它 将集中于时空、记忆、数字和执行认知功能。它的特征将在 具有脆性X全突变并在前突变中延伸到较小等位基因的儿童和成人 范围，以及未受影响(正常重复)的对照。在我们的调查中，我们将考虑两个因素的影响 连续变量：FMRP表达水平和FMR1mRNA水平，一个分类变量： 发展(童年或成年)。将与其他组件进行广泛的交互。使用 项目1我们将分享表型的神经认知规范，这将促进对 分子机制和治疗效果，我们将依赖于他们的分子和细胞 评估。在Project 2中，将提供行为和MRI评估的双向馈送，特别是 推动对FMRP和FMR1 RNA变化可能相互作用的“混合表型”的研究。数据 (和方法)在项目3和项目4之间共享将延长寿命分析，澄清神经化学 FXTAS的机制和神经进展，并推动新的MRI分析方法的发展。

Fragile X is unique among neurogenetic conditions because it is the only such disorder with a dose-response mechanism based on a single gene (CGG-repeat-dependence of phenotypes). Also, it produces varying outcomes as a result of different pathogenic mechanisms related to FMR1 gene dysregulation - low/absent FMR1 protein (FMRP) in fragile X syndrome; elevated levels of "toxic" FMR1 RNA. As a result of these characteristics, fragile X provides a unique model for developing a "molecules to mind" explanation of a neurogenetic disorder that can then be used to generate hypotheses about the genetic bases of disorders with less clear molecular mechanisms. Thus, the overall objective of this component is to understand how variations in the mutation of a single gene (FMR1) produce a spectrum of cognitive dysfunction in both childhood and adulthood. To this end, we will generate the first detailed neurocognitive profile of an integrated set of cognitive domains that preliminary data suggest are highly vulnerable to changes in the expression of FMRP. The profile will consist of data derived from hypothesis-driven experimental cognitive processing tasks and magnetic resonance imaging (MRI) methods that will produce structural, functional and connectivity measures. We will refer to this profile as the FMR1 Sensitive Neurocognitive Profile (FSNP). It will focus on spatiotemporal, memory, numerical, and executive cognitive functions. It will be characterized in children and adults who have the fragile X full mutation and extended to smaller alleles in the premutation range, and to unaffected (normal repeat) controls. In our investigations we will consider the effect of two continuous variables: FMRP expression level and FMR1 mRNA level, and one categorical variable: phase of development (childhood or adulthood). There will be extensive interaction with other components. With Project 1 we will share the neurocognitive specification of phenotypes that will foster understanding of molecular mechanisms and treatment effects and we will be dependent on their molecular and cellular assessments. With Project 2 there will be a bidirectional feed of behavioral and MRI assessments, especially to drive investigations of the "mixed phenotype" where FMRP and FMR1 RNA changes may interact. Data (and methods) shared between Projects 3 and 4 will extend lifespan analyses, clarify neurochemical mechanisms and neural progressions toward FXTAS, and drive novel MRI analysis method development.