范可尼贫血相关基因和早发性卵巢功能不全的研究进展

doi:10.12280/gjfckx.20230003

摘要/Abstract

摘要：

早发性卵巢功能不全（premature ovarian insufficiency，POI）是引起女性不孕的重要原因，发病率>1%。范可尼贫血（Fanconi anemia，FA）是一种以骨髓衰竭、出生缺陷、癌症倾向以及细胞对DNA链间交联剂敏感性增加为特征的疾病。FA相关基因以其在DNA链间交联修复的重要作用而闻名，已被证明参与生殖细胞发育，约半数的FA女性生育力受损，而FA男性基本上都不能生育。目前为止已经发现至少22个FA相关基因，FA相关基因缺陷小鼠模型的生育力受到不同程度的影响，轻者生育力下降但仍能孕育后代，重者性腺先天异常，完全丧失生育能力。FA相关基因缺陷引起的不孕病例报道也越来越多。原始生殖细胞增殖和减数分裂过程的异常被认为是引起FA患者不孕的主要原因。有研究表明参与减数分裂、DNA损伤修复及有丝分裂的基因是引起POI的一大基因家族。因此，FA相关基因在卵泡发育及生育力维持方面的作用需要得到重视。

关键词: 原发性卵巢功能不全, 范可尼贫血, DNA损伤, 减数分裂, 同源重组, 突变

Abstract:

Premature ovarian insufficiency (POI) is an important cause leading to female infertility with a prevalence of >1%. Fanconi anemia (FA) is a disease characterized by bone marrow failure, birth defects, cancer predisposition, and increased sensitivity to DNA interstrand cross-link agents. The FA related genes, known for their important role in the repair of DNA interstrand cross-links, have been shown to be involved in germ cell development. Approximately half of FA females have impaired fertility, whereas almost FA males are infertile. Up to now, at least 22 FA related genes have been found and identified. The FA gene-deficient mouse models show different effects on reproductive function. In mild cases, the mice could have their offspring despite the fertility being reduced, while in severe cases, the fertility of mice is completely lost with the abnormal gonads congenitally. There are also increasing reports of infertility caused by FA gene defects. Abnormalities in primordial germ cells proliferation and meiosis are considered to be the main causes of infertility in FA patients. Studies have shown that genes involved in meiosis, DNA damage repair and mitosis are a large family of genes that cause POI. Therefore, the role of FA genes in follicle development and fertility maintenance needs to be paid more attention.

Key words: Primary ovarian insufficiency, Fanconi anemia, DNA damage, Meiosis, Homologous recombination, Mutation

闻星星, 柴梦晗, 杨倪, 杨丹丹, 邹慧娟, 张文香, 陈蓓丽. 范可尼贫血相关基因和早发性卵巢功能不全的研究进展[J]. 国际妇产科学杂志, 2023, 50(4): 450-455.

WEN Xing-xing, CHAI Meng-han, YANG Ni, YANG Dan-dan, ZOU Hui-juan, ZHANG Wen-xiang, CHEN Bei-li. Research Progress of Fanconi Anemia Related Genes and Premature Ovarian Insufficiency[J]. Journal of International Obstetrics and Gynecology, 2023, 50(4): 450-455.

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参考文献 34

[1]	Heddar A, Ogur C, Da Costa S, et al. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine[J]. EBioMedicine, 2022, 84:104246. doi: 10.1016/j.ebiom.2022.104246. doi: 10.1016/j.ebiom.2022.104246
[2]	Chon SJ, Umair Z, Yoon MS. Premature Ovarian Insufficiency: Past, Present, and Future[J]. Front Cell Dev Biol, 2021, 9:672890. doi: 10.3389/fcell.2021.672890. doi: 10.3389/fcell.2021.672890
[3]	Ishizuka B. Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI)[J]. Front Endocrinol(Lausanne), 2021, 12:626924. doi: 10.3389/fendo.2021.626924. doi: 10.3389/fendo.2021.626924
[4]	Bhandari J, Thada PK, Puckett Y. Fanconi Anemia[EB/OL]. [2022-07-15]. https://www.researchgate.net/publication/342956278.
[5]	Auerbach AD. Fanconi anemia and its diagnosis[J]. Mutat Res, 2009, 668(1/2):4-10. doi: 10.1016/j.mrfmmm.2009.01.013. doi: 10.1016/j.mrfmmm.2009.01.013
[6]	Lemonidis K, Arkinson C, Rennie ML, et al. Mechanism, specificity, and function of FANCD2-FANCI ubiquitination and deubiquitination[J]. FEBS J, 2022, 289(16):4811-4829. doi: 10.1111/febs.16077. doi: 10.1111/febs.16077
[7]	Badra Fajardo N, Taraviras S, Lygerou Z. Fanconi anemia proteins and genome fragility: unraveling replication defects for cancer therapy[J]. Trends Cancer, 2022, 8(6):467-481. doi: 10.1016/j.trecan.2022.01.015. doi: 10.1016/j.trecan.2022.01.015 pmid: 35232683
[8]	Ceccaldi R, Sarangi P, D′Andrea AD. The Fanconi anaemia pathway: new players and new functions[J]. Nat Rev Mol Cell Biol, 2016, 17(6):337-349. doi: 10.1038/nrm.2016.48. doi: 10.1038/nrm.2016.48
[9]	Pan Y, Yang X, Zhang F, et al. A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice[J]. Mol Genet Genomics, 2021, 296(1):103-112. doi: 10.1007/s00438-020-01730-5. doi: 10.1007/s00438-020-01730-5 pmid: 33025164
[10]	Nadler JJ, Braun RE. Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells[J]. Genesis, 2000, 27(3):117-123. doi: 10.1002/1526-968x(200007)27:3＜117::aid-gene40＞3.0.co;2-7. doi: 10.1002/1526-968x(200007)27:3＜117::aid-gene40＞3.0.co;2-7 pmid: 10951504
[11]	Bakker ST, van de Vrugt HJ, Visser JA, et al. Fancf-deficient mice are prone to develop ovarian tumours[J]. J Pathol, 2012, 226(1):28-39. doi: 10.1002/path.2992. doi: 10.1002/path.2992
[12]	Agoulnik AI, Lu B, Zhu Q, et al. A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd[J]. Hum Mol Genet, 2002, 11(24):3047-3053. doi: 10.1093/hmg/11.24.3047. doi: 10.1093/hmg/11.24.3047 pmid: 12417526
[13]	Jarysta A, Riou L, Firlej V, et al. Abnormal migration behavior linked to Rac1 signaling contributes to primordial germ cell exhaustion in Fanconi anemia pathway-deficient Fancg-/- embryos[J]. Hum Mol Genet, 2021, 31(1):97-110. doi: 10.1093/hmg/ddab222. doi: 10.1093/hmg/ddab222 pmid: 34368842
[14]	Panday A, Willis NA, Elango R, et al. FANCM regulates repair pathway choice at stalled replication forks[J]. Mol Cell, 2021, 81(11):2428-2444.e6. doi: 10.1016/j.molcel.2021.03.044. doi: 10.1016/j.molcel.2021.03.044 pmid: 33882298
[15]	Bakker ST, van de Vrugt HJ, Rooimans MA, et al. Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M[J]. Hum Mol Genet, 2009, 18(18):3484-3495. doi: 10.1093/hmg/ddp297. doi: 10.1093/hmg/ddp297 pmid: 19561169
[16]	Luo Y, Hartford SA, Zeng R, et al. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling[J]. PLoS Genet, 2014, 10(7):e1004471. doi: 10.1371/journal.pgen.1004471. doi: 10.1371/journal.pgen.1004471
[17]	Jung M, Ramanagoudr-Bhojappa R, van Twest S, et al. Association of clinical severity with FANCB variant type in Fanconi anemia[J]. Blood, 2020, 135(18):1588-1602. doi: 10.1182/blood.2019003249. doi: 10.1182/blood.2019003249 pmid: 32106311
[18]	Cen C, Chen J, Lin L, et al. Fancb deficiency causes premature ovarian insufficiency in mice[J]. Biol Reprod, 2022, 107(3):790-799. doi: 10.1093/biolre/ioac103. doi: 10.1093/biolre/ioac103
[19]	Dubois EL, Guitton-Sert L, Béliveau M, et al. A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2[J]. Nucleic Acids Res, 2019, 47(14):7532-7547. doi: 10.1093/nar/gkz514. doi: 10.1093/nar/gkz514 pmid: 31219578
[20]	Sharan SK, Pyle A, Coppola V, et al. BRCA2 deficiency in mice leads to meiotic impairment and infertility[J]. Development, 2004, 131(1):131-142. doi: 10.1242/dev.00888. doi: 10.1242/dev.00888 pmid: 14660434
[21]	Hunt PA, Hassold TJ. Sex matters in meiosis[J]. Science, 2002, 296(5576):2181-2183. doi: 10.1126/science.1071907. doi: 10.1126/science.1071907 pmid: 12077403
[22]	Yang X, Zhang X, Jiao J, et al. Rare variants in FANCA induce premature ovarian insufficiency[J]. Hum Genet, 2019, 138(11/12):1227-1236. doi: 10.1007/s00439-019-02059-9. doi: 10.1007/s00439-019-02059-9
[23]	Yang Y, Guo T, Liu R, et al. FANCL gene mutations in premature ovarian insufficiency[J]. Hum Mutat, 2020, 41(5):1033-1041. doi: 10.1002/humu.23997. doi: 10.1002/humu.23997 pmid: 32048394
[24]	Fouquet B, Pawlikowska P, Caburet S, et al. A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency[J]. Elife, 2017, 6:e30490. doi: 10.7554/eLife.30490. doi: 10.7554/eLife.30490
[25]	杨亚娟. FANCI和FANCL基因在早发性卵巢功能不全发病中的作用及机制研究[D]. 济南: 山东大学, 2020.
[26]	Luo W, Guo T, Li G, et al. Variants in Homologous Recombination Genes EXO1 and RAD51 Related with Premature Ovarian Insufficiency[J]. J Clin Endocrinol Metab, 2020, 105(10):dgaa505. doi: 10.1210/clinem/dgaa505. doi: 10.1210/clinem/dgaa505
[27]	Weinberg-Shukron A, Rachmiel M, Renbaum P, et al. Essential Role of BRCA2 in Ovarian Development and Function[J]. N Engl J Med, 2018, 379(11):1042-1049. doi: 10.1056/NEJMoa1800024. doi: 10.1056/NEJMoa1800024
[28]	Turchetti D, Zuntini R, Tricarico R, et al. BRCA2 in Ovarian Development and Function[J]. N Engl J Med, 2019, 380(11):1086-1087. doi: 10.1056/NEJMc1813800. doi: 10.1056/NEJMc1813800
[29]	Yang Y, Guo J, Dai L, et al. XRCC2 mutation causes meiotic arrest, azoospermia and infertility[J]. J Med Genet, 2018, 55(9):628-636. doi: 10.1136/jmedgenet-2017-105145. doi: 10.1136/jmedgenet-2017-105145 pmid: 30042186
[30]	Zhang YX, Li HY, He WB, et al. XRCC2 mutation causes premature ovarian insufficiency as well as non-obstructive azoospermia in humans[J]. Clin Genet, 2019, 95(3):442-443. doi: 10.1111/cge.13475. doi: 10.1111/cge.13475
[31]	Yang Y, Xu W, Gao F, et al. Transcription-replication conflicts in primordial germ cells necessitate the Fanconi anemia pathway to safeguard genome stability[J]. Proc Natl Acad Sci U S A, 2022, 119(34):e2203208119. doi: 10.1073/pnas.2203208119. doi: 10.1073/pnas.2203208119
[32]	Nie Y, Wilson AF, DeFalco T, et al. FANCD2 is required for the repression of germline transposable elements[J]. Reproduction, 2020, 159(6):659-668. doi: 10.1530/REP-19-0436. doi: 10.1530/REP-19-0436 pmid: 32163912
[33]	Heddar A, Misrahi M. Concerns regarding the potentially causal role of FANCA heterozygous variants in human primary ovarian insufficiency[J]. Hum Genet, 2021, 140(4):691-694. doi: 10.1007/s00439-020-02232-5. doi: 10.1007/s00439-020-02232-5 pmid: 33151384
[34]	Heddar A, Misrahi M. Should FANCL heterozygous pathogenic variants be considered as potentially causative of primary ovarian insufficiency?[J]. Hum Mutat, 2020, 41(9):1697-1699. doi: 10.1002/humu.24077. doi: 10.1002/humu.24077 pmid: 32851770