FXPOI: Mechanisms and Modifiers

FXPOI：机制和修改器

基本信息

批准号：
10451596
负责人：
Emily Graves Allen
金额：
$ 56.48万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10451596
关键词：
5&apos Untranslated Regions Address Age Alleles Animal Model Binding Proteins Biological Bone Density CGG repeat Candidate Disease Gene Cells Child Cholesterol Clinical Coronary heart disease DNA DNA Resequencing Data Data Set Defect Development Diagnosis Disease Emotional Stress Endothelium Estrogens Etiology FMR1 FXTAS Family Fertility Fracture Fragile X Premutation Fragile X Syndrome Genes Genetic Genotype Goals Health Human Impairment Intellectual functioning disability Knowledge Length Link Longevity Medical History Menstruation Messenger RNA Modeling Molecular Mus Mutation Oocytes Osteoporosis Outcome Ovarian Ovary Pathogenicity Pathway interactions Penetrance Phenotype Population RNA Records Reproductive History Research Personnel Resources Risk Risk Factors Role Series Severities Targeted Resequencing Testing Time Tissue-Specific Gene Expression Toxic effect Transcript Translating Translations Woman Work autism spectrum disorder base body system cell type clinically significant cohort combinatorial early onset effective intervention experience family building genetic architecture genome sequencing granulosa cell human model improved induced pluripotent stem cell innovation insight mortality mouse model multidisciplinary novel offspring ovarian dysfunction phenotypic data polyglycine polypeptide primary ovarian insufficiency reproductive single-cell RNA sequencing steroid hormone subfertility synergism therapeutic target tool whole genome

项目摘要

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.

项目概要据估计，每 151 名女性中就有 1 人携带脆弱的 X 前突变等位基因，影响了超过 100 万女性我们。患有前突变的女性有可能生下患有脆性 X 综合征 (FXS) 的孩子，这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弱 X 相关原发性卵巢功能不全 (FXPOI) 的风险，其中 20-30% 经历过停止治疗 40 岁之前月经。生育能力下降是 FXPOI 最显着的后果。其他健康早期雌激素缺乏导致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、早发冠心病和总体死亡率增加。女性有前突变是一种普遍存在但尚未得到充分研究的群体。他们是被诊断出患有此病的家庭的中心脆性 X 相关疾病。该提案的重点是确定 FXPOI 的修饰符和机制。目前的数据支持与长链相关的两种非相互排斥的分子致病机制 FMR1 转录本 (rCGG) 中的预突变 CGG 重复序列：1) 可能扩展 rCGG 转录本隔离与 rCGG 结合的必需蛋白，2) 前突变 rCGG 诱导重复相关 FMR1 mRNA 5' UTR 内的非 AUG (RAN) 翻译，产生可能有毒的多肽。和关于严重性修饰符，我们之前表明前突变重复长度仅解释了约 13% 开发 FXPOI 的风险；因此，必须存在额外的修饰符。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，是由以下分子结果引起的前突变大小的 rCGG，主要是 RAN 翻译产物的毒性作用，以修饰为背景加剧 FXPOI 严重程度的基因。我们将使用一系列前突变小鼠来测试这个假设以及中心研究人员制作的人体模型和工具。目标是测试 RNA 的作用隔离和 RAN 翻译。此外，我们将建立在我们的全基因组测序结果和基础上中心研究人员生成的其他新颖数据集，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丰富的表型数据。这种独特的该中心专注于脆性 X 前突变疾病，聚集了一个多学科协作团队，在脆弱的 X 领域有重要的记录。他们的专业知识提供了新颖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相关疾病。填补这些空白将指导实施及时有效的干预措施。