The Genetics of Primary Ovarian Insufficiency

总结 原发性卵巢功能不全（POI）是卵巢功能不全的一部分，从不孕症到不孕症， 高FSH水平导致45岁之前的早期绝经，影响5-10%的女性。使用下一代 通过对家族性POI女性患者的基因测序，我们在两个基因组中发现了新的杂合突变， 家庭第一个是真核生物翻译起始因子转运蛋白eIF 4 ENIF 1， 更年期比人口平均水平早20年。第二个是POLR 2C，第三大 RNA聚合酶II的亚基，这似乎会导致每一代人更早绝经。我们现在将 应用犹他州大学开发的独特DNA序列分析软件来发现新基因 在散发性POI和家族性POI病例中的突变。此外，我们将研究POI的家庭隔离 和共病最后，我们将使用小鼠模型的eIF 4 ENIF 1停止获得突变，以确定 对卵母细胞生长和减数分裂重要的基因。具体目标1将决定基因突变的广度 在大量患有POI的妇女中，这些妇女已经经历了全外显子组测序。我们将使用小说 在犹他州大学开发的软件（VAAST、pVAAST和Phevor）中， 在两个POI群组中优先考虑老年人的变异，在第三个群组中复制（n~300）。软件能识别出罕见的， 与POI表型有密切关系的基因中的破坏性变体。具体目标2将确定 犹他州人口数据库（美国最广泛的家谱数据库）中的POI家族性病例。 将在家族性POI中分析遗传模式、相关表型和共病疾病， 确定其对整体健康的影响，并确定有POI风险的家庭。第3章将决定 使用小鼠研究eIF 4 ENIF 1终止获得突变携带者卵巢功能不全的机制 模型存在终止获得突变的多聚核糖体中差异翻译的mRNA比较 野生型将被确定。eIF 4 ENIF 1停止获得小鼠中差异翻译的mRNA 模型将突出对卵母细胞发育和减数分裂重要的基因，并将为寻找 特定目标1的基因突变。这项工作将通过阐明我们的理解来解决两个研究空白 生殖老化过渡的遗传学。它还将把生育率作为整体健康的标志， 识别与卵巢储备功能下降和POI相关的疾病。我们将能够使用家庭 病史和相关疾病，以确定有POI风险的女性。新的基因突变和途径将 通知Phevor等软件算法，该算法将使用新信息对发现的变体进行优先排序 在下一代测序，以确定更多的妇女POI的遗传原因。早期识别 将为这些妇女带来保持生育能力的潜力，并为这些妇女创造有针对性的治疗选择。

Summary Primary ovarian insufficiency (POI) is part of the continuum of ovarian dysfunction ranging from infertility with a high FSH level to early menopause before age 45 years, and affects 5-10% of women. Using next generation sequencing in women with familial POI, we have identified novel, heterozygous, stop gained mutations in two families. The first was in the eukaryotic translation initiation factor transport protein eIF4ENIF1, which causes menopause 20 years earlier than the population average. The second was in POLR2C, the third largest subunit of RNA polymerase II, which appears to cause earlier menopause in each generation. We will now apply unique DNA sequence analysis software developed at the University of Utah to discover novel gene mutations in sporadic POI and familial POI cases. In addition, we will examine the familial segregation of POI and comorbid disease. Finally, we will use a mouse model of the eIF4ENIF1 stop gained mutation to identify genes important for oocyte growth and meiosis. Specific Aim 1 will determine the breadth of genetic mutations in large populations of women with POI that have undergone whole exome sequencing. We will use novel software (VAAST, pVAAST and Phevor) developed at the University of Utah and controls recruited for health in old age to prioritize variants in two POI cohorts with replication in a third (n~300). The software identifies rare, damaging variants in genes that have a strong relationship to the POI phenotype. Specific Aim 2 will identify familial cases of POI in the Utah Population Database, the most extensive genealogical database in the U.S. The inheritance pattern, associated phenotypes and comorbid diseases will be analyzed in familial POI to determine its effect on overall health and to determine families at risk for POI. Specific Aim 3 will determine the mechanism of ovarian insufficiency in carriers of the eIF4ENIF1 stop gained mutation using a mouse model. The differentially translated mRNA in polysomes in the presence of the stop gained mutation compared to wild type will be determined. The differentially translated mRNAs in the eIF4ENIF1 stop gained mouse model will highlight the genes important for oocyte development and meiosis, and will inform the search for gene mutations in Specific Aim 1. The work will address two research gaps by illuminating our understanding of the genetics of the reproductive aging transition. It will also address fertility as a marker of overall health by identifying diseases associated with decreased ovarian reserve and POI. We will then be able to use family history and associated disorders to identify women at risk for POI. New gene mutations and pathways will inform software algorithms such as Phevor, which will use the new information to prioritize variants discovered in next generation sequencing to determine the genetic cause of POI in additional women. Early identification will bring the potential to preserve fertility and create targeted treatment options for these women.