FXPOI: Mechanisms and Modifiers

项目摘要 据估计，每151名女性中就有1名携带脆性X预突变等位基因，影响着全球100多万女性 我们。携带前突变的女性有生下脆性X综合征(FXS)的风险，FXS是最常见的 智力和发育障碍以及自闭症谱系障碍的遗传形式。这些女性也是 面临脆性X相关原发卵巢功能不全(FXPOI)的风险，20%-30%的人经历停止 40岁之前的月经。生育率下降是FXPOI最显著的后果。其他健康 早期雌激素缺乏的后果包括骨密度低，早发性骨质疏松症和骨折， 内皮功能受损，早发性冠心病，以及总体死亡率增加。女性与 前突变是一个普遍但未被研究的群体。他们是被诊断患有癌症的家庭的中心 脆性X相关疾病。这项建议的重点是确定FXPOI的修饰物和机制。 目前的数据支持与Long相关的两种非互斥的分子致病机制 FMR1转录本中的预突变CGG重复序列(RCGG)：1)潜在地扩展了rCGG转录本 隔离与rCGG结合的必需蛋白质和2)前突变rCGG诱导重复相关 在FMR1mRNA的5‘UTR区内的非8月(RAN)翻译，产生可能有毒的多肽。使用 关于严重程度的修饰因素，我们之前已经表明，前突变重复长度只解释了~13%的 发展FXPOI的风险；因此，必须存在额外的修饰语。我们强有力的初步研究支持 以下假设：FXPOI是一种多因素疾病，由 预突变大小的rCGGs，主要是RAN翻译产物的毒性效应，在修改的背景下 加重FXPOI严重程度的基因。我们将使用一系列预突变小鼠来验证这一假设 以及中心调查人员制作的人体模型和工具。目标将是测试RNA的作用 封存和RAN-翻译。此外，我们将以我们的全基因组测序结果为基础 中心研究人员生成的其他新数据集，用于识别和筛选我们的候选修饰基因 我们收集了大量的前突变和非携带者的表型数据。这个独一无二的 中心，专注于脆性X前突变疾病，聚集了一个多学科合作团队，他们 在脆性X领域有显著的记录。他们的专业知识提供了新的资源和工具来解决 与FXPOI和其他前突变相关的风险因素和途径相关的关键知识差距- 伴发的疾病。填补这些空白将指导实施及时和有效的干预措施。

Project Summary Up to an estimated 1 in 151 women carry a fragile X premutation allele, impacting over one million women in the US. Women with a premutation are at risk of having a child with fragile X syndrome (FXS), the most common genetic form of intellectual and developmental disability and autism spectrum disorder. These women are also at risk for fragile X-associated primary ovarian insufficiency (FXPOI), with 20-30% experiencing cessation of menses prior to age 40. Reduced fertility is the most significant consequence of FXPOI. Other health consequences due to early estrogen deficiency include low bone density, early-onset osteoporosis and fractures, impaired endothelial function, early-onset coronary heart disease, and increased overall mortality. Women with a premutation are a prevalent, yet understudied population. They are at the center of families diagnosed with fragile X-associated disorders. The focus of this proposal is to identify the modifiers and mechanisms of FXPOI. Current data support two non-mutually exclusive molecular pathogenic mechanisms associated with the long premutation CGG repeat track in the FMR1 transcript (rCGG): 1) expanded rCGG transcripts potentially sequester essential proteins that bind to the rCGGs and 2) the premutation rCGG induces repeat-associated non-AUG (RAN) translation within the 5' UTR of FMR1 mRNA, producing polypeptides that may be toxic. With respect to modifiers of severity, we showed previously that the premutation repeat length explains only ~13% of the risk to develop FXPOI; thus, additional modifiers of must exist. Our strong preliminary studies support the following hypothesis: FXPOI is a multifactorial disorder that results from the molecular consequence of premutation-size rCGGs, primarily the toxic effect of RAN translation products, on the background of modifying genes that exacerbate the severity of FXPOI. We will test this hypothesis using a series of premutation mouse and human models and tools generated by investigators of the Center. The goal will be to test the roles of RNA sequestration and RAN-translation. In addition, we will build on our whole genome sequencing results and on other novel datasets generated by Center investigators to identify and screen candidate modifying genes in our large cohort of premutation and non-carriers on whom we have collected rich phenotype data. This unique Center, focused on fragile X premutation disorders, has gathered a multi-disciplinary collaborative team who have significant track records in the fragile X field. Their expertise provides novel resources and tools to address critical knowledge gaps related to the risk factors and pathways associated with FXPOI and other premutation- associated disorders. Filling these gaps will guide the implementation of timely and effective interventions.