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引用次数: 0
摘要
摘要 早发性卵巢功能不全(POI)是一种常见的生殖衰老疾病,是由于卵巢功能在 40 岁之前急剧下降所致。越来越多的证据表明,遗传缺陷,尤其是与 DNA 损伤反应有关的缺陷,是导致早发性卵巢功能不全的关键因素。我们已经证明,功能性范可尼贫血(FA)通路可通过抵消复制应激来维持原始生殖细胞的快速增殖,从而建立足够的生殖储备,但这一功能对人类卵巢功能的临床影响仍有待确定。在此,我们在全外显子组测序数据库中筛选了1030例特发性卵巢炎患者中编码FA通路激活关键成分的FANCI基因,并在两名卵巢炎患者中分别发现了两对新的复合杂合变异c.[97C >T];[1865C >T]和c.[158-2A >G];[c.959A >G]。除了 c.158-2A > G 变体会导致剪接异常并导致截短突变体 p.(S54Pfs*5)外,其他错义变体不会改变 FANCI 蛋白的表达和核定位。此外,这四个变体都降低了 FANCD2 泛素化水平,增加了复制应激下的 DNA 损伤,表明 FANCI 变体损害了 FA 通路的激活和复制应激反应。这项研究首次将复制应激反应缺陷与人类 POI 的发病机制联系起来,为了解 FA 基因在卵巢功能中的重要作用提供了新的视角。
Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency
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.
期刊介绍:
Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology.
Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted.
The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.