FXPOI: Mechanisms and Modifiers

项目摘要 据估计，每151名妇女中就有1名携带脆性X前突变等位基因，影响了100多万名妇女。 我们有前突变的妇女有患脆性X综合征（FXS）的风险，这是最常见的 遗传形式的智力和发育残疾以及自闭症谱系障碍。这些女性也是 易患脆性X相关的原发性卵巢功能不全（FXPOI），20 - 30%的患者停止使用 40岁之前月经。生育能力降低是FXPOI最重要的后果。其他健康 早期雌激素缺乏的后果包括低骨密度，早发性骨质疏松症和骨折， 内皮功能受损、早发冠心病和总体死亡率增加。妇女 前突变是一个普遍的，但研究不足的群体。他们是被诊断为 脆性X相关疾病该提案的重点是确定FXPOI的修饰剂和机制。 目前的数据支持两个非相互排斥的分子致病机制与长期 FMR 1转录本（rCGG）中的前突变CGG重复轨道：1）扩增的rCGG转录本可能 螯合与rCGG结合的必需蛋白，2）前突变rCGG诱导重复相关的 在FMR 1 mRNA的5'UTR内的非AUG（RAN）翻译，产生可能有毒的多肽。与 关于严重程度的修饰语，我们先前表明，前突变重复序列长度仅解释了~13%的 开发FXPOI的风险;因此，必须存在额外的修改器。我们强大的初步研究支持 以下假设：FXPOI是一种多因素疾病，由以下因素的分子后果引起： 前突变大小的rCGG，主要是RAN翻译产物的毒性作用，在修饰的背景下， 这些基因加剧了FXPOI的严重性。我们将使用一系列前突变小鼠来检验这一假设。 以及中心研究人员制作的人体模型和工具。我们的目标是测试RNA在 螯合和RAN翻译。此外，我们将建立在我们的全基因组测序结果和 中心研究人员生成的其他新数据集，以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。这种独特 中心，专注于脆性X前突变障碍，已经聚集了一个多学科的合作团队， 在易碎品领域有着良好的记录他们的专业知识提供了新的资源和工具， 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- 相关疾病。填补这些空白将指导及时和有效的干预措施的实施。

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.