Abstract：
Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.
摘要：
过早卵巢功能不全（POI）是一种常见的生殖衰老疾病，原因是在40岁之前卵巢功能急剧下降。越来越多的证据表明遗传缺陷，特别是那些与DNA损伤反应有关的，是POI的一个关键因素。我们已经证明，功能性范可尼贫血（FA）途径维持原始生殖细胞的快速增殖，以通过抵消复制应激来建立足够的生殖储备，但这种功能在人类卵巢功能中的临床意义仍有待确定。这里,我们筛选了FANCI基因,编码FA通路激活的关键成分，在我们1030名特发性POI患者的全外显子组测序数据库中，并鉴定了两对新的复合杂合变体，c。[97C>T]；[1865C>T]和c。[158-2A>G]；[c.959A>G]，在两名POI患者中，分别。错义变体不会改变FANCI蛋白表达和核定位，除了变体c.158-2A>G引起异常剪接并导致截短的突变体p。（S54Pfs*5）。此外，这四种变体都降低了FANCD2泛素化水平，并增加了复制应激下的DNA损伤，提示FANCI变异体损害FA通路激活和复制应激反应。本研究首先将复制应激反应缺陷与人类POI的发病机制联系起来，为FA基因在卵巢功能中的重要作用提供了新的见解。
