Fragile X Spectrum as Model for Neurogenetic Mechanisms of Cognitive Dysfunction

脆性X染色体在神经遗传性疾病中是独一无二的，因为它是唯一具有剂量反应的疾病 基于单基因的机制（表型的CGG重复依赖性）。此外，它还产生不同的 与FMR 1基因失调相关的不同致病机制导致的结果-低/不存在 脆性X综合征中的FMR 1蛋白（FMRP）;“毒性”FMR 1 RNA水平升高。由于这些 脆性X的特征，脆性X提供了一个独特的模型，为发展一个“分子的头脑”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设 分子机制不太清楚。因此，该组件的总体目标是了解如何 单个基因（FMR 1）突变的变异在两个基因中都产生了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， 初步数据表明，一套完整的认知领域非常容易受到环境变化的影响。 FMRP的表达。该配置文件将包括来自假设驱动的实验认知的数据， 处理任务和磁共振成像（MRI）方法，将产生结构，功能和 连通性措施。我们将此配置文件称为FMR 1敏感神经认知配置文件（FSNP）。它 将侧重于时空，记忆，数字和执行认知功能。它的特点是 具有脆性X完全突变并在前突变中扩展到较小等位基因的儿童和成人 范围，以及未受影响的（正常重复）对照。在我们的研究中，我们将考虑两个影响 连续变量：FMRP表达水平和FMR 1 mRNA水平，以及一个分类变量： 发展（童年或成年）。将与其他组成部分进行广泛的互动。与 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。在项目2中，将有一个双向的行为和MRI评估，特别是 以推动FMRP和FMR 1 RNA变化可能相互作用的“混合表型”的研究。数据 (and项目3和项目4之间共享的方法）将延长寿命分析，澄清神经化学 机制和神经向FXTAS的进展，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.