Fragile X Premutations, Mechanisms and Modifiers

脆性X突变-机制和修饰 脆性X相关疾病是一组异质性的条件所产生的改变 FMR 1基因内多态性CGG重复序列的大小、含量和表观遗传状态。 FMR 1 CGG重复序列在近30年前被描述为第一个重复序列扩增障碍， 扩张是神经、生殖和神经发育的重要原因， 疾病以及理解重复扩张和机制的原型， 从而导致功能障碍过去几十年的工作描绘了 脆性X蛋白，FMRP，以及其损失的后果和探索的毒性增益， 功能机制（RNA介导的毒性通过蛋白螯合，和蛋白介导的 来自转录CGG引起的重复相关非AUG（RAN）翻译的毒性 重复。尽管做出了这些努力，我们仍然缺乏有效的治疗方法来治疗任何主要的脆性X- 相关疾病。 在这里，我们提出了一个范式转变，我们的方法FX相关的疾病。而不是 仅专注于特定疾病（脆性X综合征（FXS），脆性X相关 震颤/共济失调综合征（FXTAS）和脆性X相关的原发性卵巢功能不全 （FXPOI）），中心结构使我们能够直接参与之间的机械串扰 条件和FMR 1基因座和相关的重复扩增障碍之间的关系。我们的中央 一种假说认为，对临床疾病背后的遗传因素有更深入的了解， 前突变相关疾病的发病和复发以及天然CGG的探索 重复功能将揭示新的见解，既重复如何导致疾病， 可能是治疗靶点由一个多学科团队领导， 脆弱的X领域，我们将解决这个假设在三个有凝聚力的项目都集中在 通过使用数据驱动的基因组学和生物信息学方法， 与新兴的工具和综合模型系统。通过汇集我们的大量数据和专业知识 和资源，我们将追求更深入地了解FX前突变致病性 机制，并确定了一系列强大的和可行的治疗发展的目标 脆性X染色体相关疾病

Fragile X Premutations- Mechanisms and Modifiers Fragile X-associated disorders are a heterogeneous group of conditions arising from alterations in the size, content, and epigenetic state of a polymorphic CGG repeat within the FMR1 gene. Described as the first repeat expansion disorder nearly 30 years ago, FMR1 CGG repeat expansions are both an important cause of neurological, reproductive and neurodevelopmental disease as well as an archetype for understanding repeat expansions and the mechanisms by which they elicit dysfunction. Work over past decades delineated the native functions of the fragile X protein, FMRP, and the consequences of its loss and the explored toxic gain-of function mechanisms (RNA-mediated toxicity via protein sequestration, and protein mediated toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG repeats. Despite these efforts, we still lack effective therapies for any of the cardinal Fragile X- associated disorders. Here we propose a paradigm shift in our approach to FX associated disorders. Rather than focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI)), the Center structure enables us to directly engage the mechanistic cross-talk between conditions and between the FMR1 locus and related repeat expansion disorders. Our central hypothesis is that a deeper understanding of genetic factors which underlie clinical disease onset and penetrance in premutation associated disorders and an exploration of native CGG repeat functions will reveal novel insights into both how repeats cause disease and how they might be targeted therapeutically. Led by a multidisciplinary team featuring many leaders in the Fragile X field, we will address this hypothesis in three cohesive projects all focused on premutation disorders by using data-driven genomic and bioinformatics approaches coupled with emerging tools and integrative model systems. By pooling our substantial data, expertise and resources, we will pursue a deeper understanding of FX premutation pathogenic mechanisms and define a series of robust and viable targets for therapeutic development across Fragile X-associated disorders.