Genetics of Human Ovarian Failure

描述（由申请人提供）：卵巢早衰（POF）困扰着1-2%的女性，遗传因素对POF的贡献高达70%。大多数卵巢功能衰竭病例是由于相关不孕症而散发的。绝大多数女性的POF是非综合征性的，即，它只影响卵巢功能。在卵巢中优先表达的少数基因突变，如促卵泡激素受体（FSHR）和骨形态发生蛋白15（BMP 15），已被证明在功能上折磨一些女性POF。在过去的十年中，已经发现了许多在卵母细胞中优先表达的基因。由于人类卵母细胞很难获得和研究，因此小鼠研究在鉴定卵母细胞中优先表达的基因方面处于领先地位。主要由我们实验室产生的小鼠基因敲除表明，转录调节因子Nobox、Sohlh 1和Figla优先在生殖系中表达，并导致小鼠卵巢功能衰竭。在过去的2年里，我们招募了散发性和家族性卵巢早衰的妇女，以确定人类卵巢功能衰竭的遗传学。我们已经招募了100多名女性，并将继续招募更多的受试者。我们的初步数据显示，NOBOX和FIGLA的突变可导致人类卵巢衰竭。因此，在卵母细胞中优先表达的基因是POF遗传原因的理想候选者。我们确定了10个候选基因优先在小鼠卵母细胞中表达，这些基因在人类中是保守的，属于NOBOX和FIGLA调控的途径。我们假设，分析这十个基因的编码和调控序列，优先在卵母细胞中表达，将揭示新的突变和常见的等位基因变异，导致卵巢功能衰竭的模式。此外，我们将利用寡核苷酸阵列比较基因组杂交来鉴定与卵巢功能衰竭相关的拷贝数变异。公共卫生相关性：卵巢功能衰竭对妇女的生殖潜力、心理健康、骨矿化、心血管健康和寿命产生不利影响。我们建议通过分析卵母细胞特异性基因的突变和基因组的结构变化来确定人类卵巢功能衰竭的遗传病因。人类卵巢功能衰竭的新遗传标记的鉴定将有助于确定妇女的医疗发病率和死亡率增加的风险，以及为他们提供早期的医疗干预，以保护他们的生殖选择。

DESCRIPTION (provided by applicant): Premature ovarian failure (POF) afflicts 1-2% of women, and genetics contributes as much as 70% to POF. Most cases of ovarian failure are sporadic due to associated infertility. POF in the vast majority of women is non-syndromic, i.e., it only affects ovarian function. Mutations in few genes preferentially expressed in the ovary, such as follicle stimulating hormone receptor (FSHR) and bone morphogenetic protein 15 (BMP15), have been functionally shown to afflict some women with POF. Over the past decade a number of genes preferentially expressed in oocytes have been discovered. Mouse studies have led the way in identifying genes preferentially expressed in oocytes, because human oocytes are difficult to obtain and study. Mouse knockouts, generated mainly by our laboratory, show that transcriptional regulators Nobox, Sohlh1 and Figla, are preferentially expressed in the germline and cause ovarian failure in mice. Over the past 2 years, we have enrolled women with sporadic and familial POF to determine the genetics of human ovarian failure. We have enrolled over 100 women and continue to enroll more subjects. Our preliminary data show that mutations in NOBOX and FIGLA can cause human ovarian failure. Therefore, genes preferentially expressed in oocytes represent ideal candidates for genetic causes of POF. We identified ten candidate genes preferentially expressed in mouse oocytes that are conserved in humans and belong to the pathway regulated by NOBOX and FIGLA. We hypothesize that profiling the coding and regulatory sequences of these ten genes preferentially expressed in oocytes will reveal novel mutations and patterns of common allelic variants that lead to ovarian failure. In addition, we will utilize oligonucleotide array comparative genomic hybridization to identify copy number variants that associate with ovarian failure. PUBLIC HEALTH RELEVANCE: Ovarian failure adversely affects women's reproductive potential, psychosocial well-being, bone mineralization, cardiovascular health and life span. We propose to determine genetic etiology of human ovarian failure through analyses of mutations in oocyte-specific genes and structural changes in the genome. Identification of novel genetic markers for human ovarian failure will help identify women at risk for increased medical morbidity and mortality as well as offer them earlier medical interventions to preserve their reproductive options.