Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency
Objective Premature ovarian insufficiency (POI) is defined as the depletion of ovarian function before 40 years of age, affecting approximately 3.7% of women in their reproductive age worldwide. Previous studies revealed several genes involved in the Fanconi anaemia (FA) pathway participate in the p...
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BMJ Publishing Group
2025-05-01
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| Series: | Gynecology and Obstetrics Clinical Medicine |
| Online Access: | https://gocm.bmj.com/content/5/2/e000208.full |
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| author | Chunmei Zhang Ting Guo Xin Liang Yingying Qin Anmiao Sun Xinmiao He Mengchun Hu Hongyuan Liu Xiaowei Wu Manting Yang Runxin Yao Shidou Zhao Xue Jiao |
| author_facet | Chunmei Zhang Ting Guo Xin Liang Yingying Qin Anmiao Sun Xinmiao He Mengchun Hu Hongyuan Liu Xiaowei Wu Manting Yang Runxin Yao Shidou Zhao Xue Jiao |
| author_sort | Chunmei Zhang |
| collection | DOAJ |
| description | Objective Premature ovarian insufficiency (POI) is defined as the depletion of ovarian function before 40 years of age, affecting approximately 3.7% of women in their reproductive age worldwide. Previous studies revealed several genes involved in the Fanconi anaemia (FA) pathway participate in the pathogenesis of POI, such as FANCA and FANCM. FA pathway maintains rapid proliferation in the developing primordial germ cells by deregulating transcription-replication conflicts, which is crucial for the establishment of sufficient ovarian reserve. FANCJ encodes a DNA helicase located downstream of the FA pathway promoting DNA damage repair and cell proliferation. Recently, two heterozygous FANCJ missense variants have been reported in patients with POI, suggesting haploinsufficiency of FANCJ participates in the pathogenesis of the disease. In this study, to further explore the contribution of FANCJ variants in POI, we reported a rare homozygous FANCJ start-loss variation in one patient with POI and illustrated its pathogenicity by in vitro functional studies.Methods The loss-of-function (LoF) variants of FANCJ were screened in our internal whole-exome sequencing (WES) database of POI. Sanger sequencing and WES analysis were employed on the proband and the patient’s family members to illustrate the origin of the bi-allelic variant. Cycloheximide chase assay was performed to demonstrate the impact of the variant on the protein stability of FANCJ. Protein ubiquitination assay was performed to confirm the accelerated degradation pathway of FANCJ protein.Results Through the variation screening, a bi-allelic variant of FANCJ (NM_032043.3:c.1A>G, p.Met1Val) was identified in one case. The functional study showed that the start-loss variant affected FANCJ protein stability by accelerated protein degradation through the ubiquitin-proteasome pathway.Conclusion Our findings provide further genetic evidence of the FANCJ variant participating in the pathogenesis of POI, expand the inherited mode and highlight the essential role of the FA pathway in maintaining ovarian function. |
| format | Article |
| id | doaj-art-c9f65b1ae40b4ad0b1a623495a077f4e |
| institution | DOAJ |
| issn | 2097-0587 2667-1646 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMJ Publishing Group |
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| series | Gynecology and Obstetrics Clinical Medicine |
| spelling | doaj-art-c9f65b1ae40b4ad0b1a623495a077f4e2025-08-20T03:05:49ZengBMJ Publishing GroupGynecology and Obstetrics Clinical Medicine2097-05872667-16462025-05-015210.1136/gocm-2025-000208Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiencyChunmei Zhang0Ting Guo1Xin Liang2Yingying Qin3Anmiao Sun4Xinmiao He5Mengchun Hu6Hongyuan Liu7Xiaowei Wu8Manting Yang9Runxin Yao10Shidou Zhao11Xue Jiao124 Dongfang Municipal Health Commission, Dongfang, Hainan, ChinaDepartment of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing, ChinaShandong University National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, Shandong, ChinaprofessorShandong Provincial Clinical Research Center for Reproductive Health, Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaShandong Provincial Clinical Research Center for Reproductive Health, Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaShandong Provincial Clinical Research Center for Reproductive Health, Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaShandong University State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Jinan, Shandong, ChinaObjective Premature ovarian insufficiency (POI) is defined as the depletion of ovarian function before 40 years of age, affecting approximately 3.7% of women in their reproductive age worldwide. Previous studies revealed several genes involved in the Fanconi anaemia (FA) pathway participate in the pathogenesis of POI, such as FANCA and FANCM. FA pathway maintains rapid proliferation in the developing primordial germ cells by deregulating transcription-replication conflicts, which is crucial for the establishment of sufficient ovarian reserve. FANCJ encodes a DNA helicase located downstream of the FA pathway promoting DNA damage repair and cell proliferation. Recently, two heterozygous FANCJ missense variants have been reported in patients with POI, suggesting haploinsufficiency of FANCJ participates in the pathogenesis of the disease. In this study, to further explore the contribution of FANCJ variants in POI, we reported a rare homozygous FANCJ start-loss variation in one patient with POI and illustrated its pathogenicity by in vitro functional studies.Methods The loss-of-function (LoF) variants of FANCJ were screened in our internal whole-exome sequencing (WES) database of POI. Sanger sequencing and WES analysis were employed on the proband and the patient’s family members to illustrate the origin of the bi-allelic variant. Cycloheximide chase assay was performed to demonstrate the impact of the variant on the protein stability of FANCJ. Protein ubiquitination assay was performed to confirm the accelerated degradation pathway of FANCJ protein.Results Through the variation screening, a bi-allelic variant of FANCJ (NM_032043.3:c.1A>G, p.Met1Val) was identified in one case. The functional study showed that the start-loss variant affected FANCJ protein stability by accelerated protein degradation through the ubiquitin-proteasome pathway.Conclusion Our findings provide further genetic evidence of the FANCJ variant participating in the pathogenesis of POI, expand the inherited mode and highlight the essential role of the FA pathway in maintaining ovarian function.https://gocm.bmj.com/content/5/2/e000208.full |
| spellingShingle | Chunmei Zhang Ting Guo Xin Liang Yingying Qin Anmiao Sun Xinmiao He Mengchun Hu Hongyuan Liu Xiaowei Wu Manting Yang Runxin Yao Shidou Zhao Xue Jiao Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency Gynecology and Obstetrics Clinical Medicine |
| title | Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency |
| title_full | Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency |
| title_fullStr | Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency |
| title_full_unstemmed | Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency |
| title_short | Bi-allelic variation of FANCJ (BRIP1) identified in premature ovarian insufficiency |
| title_sort | bi allelic variation of fancj brip1 identified in premature ovarian insufficiency |
| url | https://gocm.bmj.com/content/5/2/e000208.full |
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