Fragile X Premutations, Mechanisms and Modifiers

脆性X先天突变--机制和修饰物 脆性X相关疾病是由改变引起的一组不同的疾病 在FMR1基因内的多态CGG重复的大小、内容和表观遗传状态。 近30年前被描述为第一个重复扩张性疾病，FMR1 CGG重复 扩张是神经、生殖和神经发育的重要原因。 疾病，以及一个原型，以了解重复扩张和机制 它们会引起功能障碍。过去几十年的工作描绘了 脆性X蛋白，FMRP，及其丢失的后果和探索的毒性获得- 作用机制(RNA通过蛋白质隔离和蛋白质介导的毒性 转录的CGG引起的重复相关非Aug(RAN)翻译毒性 重复着。尽管做出了这些努力，我们仍然缺乏有效的治疗任何一种主要的脆性X- 伴发的疾病。 在这里，我们提出了一种治疗外汇相关疾病的方法的范式转变。而不是 只关注特定疾病(脆性X综合征(FXS)、脆性X相关 震颤/共济失调综合征(FXTAS)与脆性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机械串扰 FMR1基因座与相关的重复扩张性疾病之间的关系。我们的中央 假设是对临床疾病背后的遗传因素有了更深入的了解 突变前相关疾病的发病和外显性及遗传性CGG的探讨 重复功能将揭示重复如何导致疾病以及它们如何导致疾病的新见解 可能是治疗上的靶点。由一个多学科团队领导，团队中有许多领导者 脆弱的X领域，我们将在三个凝聚力项目中解决这个假设，这些项目都集中在 结合使用数据驱动的基因组学和生物信息学方法的前突变障碍 使用新兴的工具和综合模型系统。通过汇集我们的大量数据、专业知识 和资源，我们将更深入地了解FX前突变致病机理 机制，并为治疗开发定义了一系列强大和可行的目标 跨越脆弱的X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.