Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination
Abstract The DNA damage response plays a pivotal role in ovarian aging. Breast cancer susceptibility gene 2 (BRCA2), which participates in homologous recombination (HR), is a key regulator of natural menopause. Rare BRCA2 variants have been identified in patients with premature ovarian insufficiency...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08426-9 |
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| author | Xinyi Wu Qian Zhang Chang Li Shuning Zhuang Hongyuan Liu Xue Jiao Shidou Zhao Yingying Qin Ting Guo |
| author_facet | Xinyi Wu Qian Zhang Chang Li Shuning Zhuang Hongyuan Liu Xue Jiao Shidou Zhao Yingying Qin Ting Guo |
| author_sort | Xinyi Wu |
| collection | DOAJ |
| description | Abstract The DNA damage response plays a pivotal role in ovarian aging. Breast cancer susceptibility gene 2 (BRCA2), which participates in homologous recombination (HR), is a key regulator of natural menopause. Rare BRCA2 variants have been identified in patients with premature ovarian insufficiency (POI). However, the underlying molecular mechanisms are not well understood. Using a viable mouse model, Brca2 c.68-1G>C/c.4384-4394del , carrying compound heterozygous variants mirroring the ones identified in a POI pedigree, we illustrated the essential role of BRCA2 in primordial follicle pool establishment. Germline deficiency of BRCA2 did not affect primordial germ cell (PGC) proliferation but impaired the recruitment of RAD51 and DMC1 to programmed DNA double-strand breaks (DSBs) during meiotic HR, causing postnatal oocyte depletion. Moreover, Brca2 c.68-1G>C/c.4384-4394del mice presented increased tumor susceptibility. These findings confirmed the pathogenicity of BRCA2 biallelic variants in POI, revealing the dual impact on germ cell development and somatic cancer risk, underscoring the necessity of tumor surveillance in POI patients with BRCA2 mutations. |
| format | Article |
| id | doaj-art-d00295ff9a3448f0bbccb512da5ec344 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-d00295ff9a3448f0bbccb512da5ec3442025-08-20T03:43:26ZengNature PortfolioCommunications Biology2399-36422025-07-018111210.1038/s42003-025-08426-9Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombinationXinyi Wu0Qian Zhang1Chang Li2Shuning Zhuang3Hongyuan Liu4Xue Jiao5Shidou Zhao6Yingying Qin7Ting Guo8State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong UniversityAbstract The DNA damage response plays a pivotal role in ovarian aging. Breast cancer susceptibility gene 2 (BRCA2), which participates in homologous recombination (HR), is a key regulator of natural menopause. Rare BRCA2 variants have been identified in patients with premature ovarian insufficiency (POI). However, the underlying molecular mechanisms are not well understood. Using a viable mouse model, Brca2 c.68-1G>C/c.4384-4394del , carrying compound heterozygous variants mirroring the ones identified in a POI pedigree, we illustrated the essential role of BRCA2 in primordial follicle pool establishment. Germline deficiency of BRCA2 did not affect primordial germ cell (PGC) proliferation but impaired the recruitment of RAD51 and DMC1 to programmed DNA double-strand breaks (DSBs) during meiotic HR, causing postnatal oocyte depletion. Moreover, Brca2 c.68-1G>C/c.4384-4394del mice presented increased tumor susceptibility. These findings confirmed the pathogenicity of BRCA2 biallelic variants in POI, revealing the dual impact on germ cell development and somatic cancer risk, underscoring the necessity of tumor surveillance in POI patients with BRCA2 mutations.https://doi.org/10.1038/s42003-025-08426-9 |
| spellingShingle | Xinyi Wu Qian Zhang Chang Li Shuning Zhuang Hongyuan Liu Xue Jiao Shidou Zhao Yingying Qin Ting Guo Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination Communications Biology |
| title | Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| title_full | Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| title_fullStr | Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| title_full_unstemmed | Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| title_short | Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| title_sort | biallelic brca2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination |
| url | https://doi.org/10.1038/s42003-025-08426-9 |
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