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.
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Data availability
The raw sequencing data of 1030 patients with idiopathic POI in this study are available in the Genome Sequence Archive (https://ngdc.cncb.ac.cn/gsa-human/), under the accession number HRA003245 (project: PRJCA012479).
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Funding
This work was supported by grants from the National Key Research and Development Program of China (2022YFC2703800 and 2021YFC2700100), National Natural Science Foundation of China (32170867, 32370906, 32200697 and 82371645), National Natural Science Foundation for Distinguished Young Scholars (82125014), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Shandong Provincial Key Research and Development Program (2020ZLYS02), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211370) and Qilu Young Scholars Program of Shandong University.
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YY and SZ designed the study and guided the writing of the manuscript. LC and XH performed the experiments, analyzed the results, and wrote the manuscript. JR and CW performed the experiments. TG conducted the sequencing data analysis. FY performed the experiments and revised the manuscript. YQ and Z-JC provided guidance and supervised the research.
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Cao, L., He, X., Ren, J. et al. Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency. Hum. Genet. 143, 357–369 (2024). https://doi.org/10.1007/s00439-024-02650-9
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DOI: https://doi.org/10.1007/s00439-024-02650-9