FMR1基因突变与女性生殖能力和妊娠结局

doi:10.12280/gjszjk.20200251

摘要/Abstract

摘要：

近年来原发性卵巢功能不全（primary ovarian insufficiency,POI）、不明原因的早期自然流产、复发性流产、胚胎停育等生育能力低下和反复生育失败的疾病越来越多,女性生殖健康也日益受到关注。脆性X智力低下1（fragile X mental retardation 1,FMR1）基因参与胚胎发育的基因调控过程,该基因的突变可引起多种女性生殖健康疾病,且与绝经年龄相关。因此FMR1基因的筛查对协助诊疗女性生殖健康疾病有重要的临床价值,也为疾病的早期预防、诊断和治疗提供了新思路。

关键词: 原发性卵巢功能不全, 重复序列, 核酸, 突变, 脆性X智力低下蛋白质, 流产, 自然, 绝经, 过早, 脆性X智力低下1基因

Abstract:

In recent years, there are more and more diseases of low fertility and repeated fertility failure, such as primary ovarian insufficiency (POI), unexplained early spontaneous abortion, recurrent abortion, embryo termination and so on. Fragile X mental retardation 1 (FMR1) gene is involved in the gene regulation of embryonic development. The mutations of FMR1 gene can cause a variety of female reproductive health diseases. The mutations of FMR1 gene are also related to menopausal age. Therefore, the screening of FMR1 gene has important clinical value in the diagnosis and treatment of female reproductive diseases, and also provides new ideas for the early prevention, diagnosis and treatment of the disease.

Key words: Primary ovarian insufficiency, Repetitive sequences, nucleic acid, Mutation, Fragile X mental retardation protein, Abortion, spontaneous, Menopause, premature, Fragile X mental retardation 1 gene

王美雲, 周建政. FMR1基因突变与女性生殖能力和妊娠结局[J]. 国际生殖健康/计划生育, 2021, 40(1): 64-68.

WANG Mei-yun, ZHOU Jian-zheng. FMR1 Gene Mutations and Female Fertility and Pregnancy Outcome[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(1): 64-68.

参考文献 36

[1]	Hagerman RJ, Protic D, Rajaratnam A, et al. Fragile X-Associated Neuropsychiatric Disorders (FXAND)[J]. Front Psychiatry, 2018,9:564. doi: 10.3389/fpsyt.2018.00564.
[2]	Rehnitz J, Alcoba DD, Brum IS, et al. FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve[J]. Reprod Biol Endocrinol, 2018,16(1):65. doi: 10.1186/s12958-018-0383-5.
[3]	Jankowska K. Premature ovarian failure[J]. Prz Menopauzalny, 2017,16(2):51-56. doi: 10.5114/pm.2017.68592.
[4]	Jiao X, Zhang H, Ke H, et al. Premature Ovarian Insufficiency: Phenotypic Characterization Within Different Etiologies[J]. J Clin Endocrinol Metab, 2017,102(7):2281-2290. doi: 10.1210/jc.2016-3960.
[5]	Jeng EI, Martin TD. J-Mart:aortic valve replacement with Florida sleeve aortic root reconstruction[J]. Eur J Cardiothorac Surg, 2020,58(6):1304-1305. doi: 10.1093/ejcts/ezaa236.
[6]	Gao F, Huang W, You Y, et al. Development of Chinese genetic reference panel for Fragile X Syndrome and its application to the screen of 10, 000 Chinese pregnant women and women planning pregnancy[J]. Mol Genet Genomic Med, 2020,8(6):e1236. doi: 10.1002/mgg3.1236.
[7]	Man L, Lekovich J, Rosenwaks Z, et al. Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations[J]. Front Mol Neurosci, 2017,10:290. doi: 10.3389/fnmol.2017.00290.
[8]	Rose BI, Brown SE. An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency[J]. J Assist Reprod Genet, 2020,37:1313-1322. doi: 10.1007/s10815-020-01774-x.
[9]	Suardi GAM, Haddad LA. FMRP ribonucleoprotein complexes and RNA homeostasis[J]. Adv Genet, 2020,105:95-136. doi: 10.1016/bs.adgen.2020.01.001.
[10]	Lekovich J, Man L, Xu K, et al. CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve[J]. Genet Med, 2018,20(9):957-964. doi: 10.1038/gim.2017.220.
[11]	Huang J, Zhang W, Liu Y, et al. Association between the FMR1 CGG repeat lengths and the severity of idiopathic primary ovarian insufficiency: a meta analysis[J]. Artif Cells Nanomed Biotechnol, 2019,47(1):3116-3122. doi: 10.1080/21691401.2019.1645153.
[12]	Asadi R, Omrani MD, Ghaedi H, et al. Premutations of FMR1 CGG repeats are not related to idiopathic premature ovarian failure in Iranian patients: A case control study[J]. Gene, 2018,676:189-194. doi: 10.1016/j.gene.2018.07.034.
[13]	Barasoain M, Barrenetxea G, Huerta I, et al. Study of FMR1 gene association with ovarian dysfunction in a sample from the Basque Country[J]. Gene, 2013,521(1):145-149. doi: 10.1016/j.gene.2013.03.032.
[14]	Kline JK, Kinney AM, Levin B, et al. Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age[J]. Menopause, 2014,21(7):740-748. doi: 10.1097/GME.0000000000000139.
[15]	Eslami A, Farahmand K, Totonchi M, et al. FMR1 premutation: not only important in premature ovarian failure but also in diminished ovarian reserve[J]. Hum Fertil(Camb), 2017,20(2):120-125. doi: 10.1080/14647273.2016.1255356.
[16]	Yang W, Fan C, Chen L, et al. Pathological Effects of the FMR1 CGG-Repeat Polymorphism (5-55 Repeat Numbers): Systematic Review and Meta-Analysis[J]. Tohoku J Exp Med, 2016,239(1):57-66. doi: 10.1620/tjem.239.57.
[17]	Lu CL, Li R, Chen XN, et al. The ′normal′ range of FMR1 triple CGG repeats may be associated with primary ovarian insufficiency in China[J]. Reprod Biomed Online, 2017,34(2):175-180. doi: 10.1016/j.rbmo.2016.11.001.
[18]	Elizur SE, Lebovitz O, Derech-Haim S, et al. Elevated levels of FMR1 mRNA in granulosa cells are associated with low ovarian reserve in FMR1 premutation carriers[J]. PLoS One, 2014,9(8):e105121. doi: 10.1371/journal.pone.0105121.
[19]	Elizur SE, Friedman Gohas M, Dratviman-Storobinsky O, et al. Pathophysiology Mechanisms in Fragile-X Primary Ovarian Insufficiency[J]. Methods Mol Biol, 2019,1942:165-171. doi: 10.1007/978-1-4939-9080-1_14.
[20]	Sellier C, Buijsen R, He F, et al. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome[J]. Neuron, 2017,93(2):331-347. doi: 10.1016/j.neuron.2016.12.016.
[21]	Friedman-Gohas M, Elizur SE, Dratviman-Storobinsky O, et al. FMRpolyG accumulates in FMR1 premutation granulosa cells[J]. J Ovarian Res, 2020,13(1):22. doi: 10.1186/s13048-020-00623-w.
[22]	Huang G, Zhu H, Wu S, et al. Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome[J]. Front Genet, 2019,10:446. doi: 10.3389/fgene.2019.00446.
[23]	Tu J, Chen Y, Li Z, et al. Long non-coding RNAs in ovarian granulosa cells[J]. J Ovarian Res, 2020,13(1):63. doi: 10.1186/s13048-020-00663-2.
[24]	Domniz N, Ries-Levavi L, Cohen Y, et al. Absence of AGG Interruptions Is a Risk Factor for Full Mutation Expansion Among Israeli FMR1 Premutation Carriers[J]. Front Genet, 2018,9:606. doi: 10.3389/fgene.2018.00606.
[25]	Ardui S Race V de Ravel T, et al. Detecting AGG Interruptions in Females With a FMR1 Premutation by Long-Read Single-Molecule Sequencing: A 1 Year Clinical Experience[J]. Front Genet, 2018,9:150. doi: 10.3389/fgene.2018.00150.
[26]	王新花. 新建超声模型对妊娠不良结局的预测价值及FMR1基因与流产的关系探讨[D]. 济南:山东大学, 2018.
[27]	陈蔚琳, 金力, 武淑英, 等. FMR1基因CGG重复序列频度与反复生育失败或卵巢早衰妇女的相关性研究[J]. 生殖医学杂志, 2018,27(10):946-951. doi : 10.3969/j.issn.1004-3845.2018.10.004.
[28]	冯旺琴, 陈素文, 武淑英, 等. FMR1基因CGG重复序列多态性与不明原因早期自然流产的相关性研究[J]. 生殖医学杂志, 2019,28(1):12-17. doi : 10.3969/j.issn.1004-3845.2019.01.003.
[29]	Dean DD, Agarwal S, Muthuswamy S. Defining the role of FMR1 gene in unexplained recurrent spontaneous abortion[J]. J Assist Reprod Genet, 2019,36(11):2245-2250. doi: 10.1007/s10815-019-01591-x.
[30]	Fragkos M, Bili H, Ntelios D, et al. Are expanded alleles of the FMR1 gene related to unexplained recurrent miscarriages?[J]. Hippokratia, 2018,22(3):132-136.
[31]	Gleicher N, Weghofer A, Barad DH. A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone[J]. Fertil Steril, 2009,91(5):1700-1706. doi: 10.1016/j.fertnstert.2008.01.098.
[32]	Mailick MR, Hong J, Greenberg J, et al. Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions[J]. Am J Med Genet B Neuropsychiatr Genet, 2014,165B(8):705-711. doi: 10.1002/ajmg.b.32277.
[33]	Ruth KS, Bennett CE, Schoemaker MJ, et al. Length of FMR1 repeat alleles within the normal range does not substantially affect the risk of early menopause[J]. Hum Reprod, 2016,31(10):2396-2403. doi: 10.1093/humrep/dew204.
[34]	Tang R, Chen R, Luo M, et al. Chinese women with 29-30 FMR1 CGG repeats have an earlier menopause[J]. Climacteric, 2020,23(3):298-305. doi: 10.1080/13697137.2020.1727877.
[35]	Pastore LM, Young SL, Manichaikul A, et al. Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study)[J]. Fertil Steril, 2017,107(1):205-211.e1. doi: 10.1016/j.fertnstert.2016.09.032.
[36]	Committee on Genetics. Committee Opinion No. 691: Carrier Screening for Genetic Conditions[J]. Obstet Gynecol, 2017,129(3):e41-e55. doi: 10.1097/AOG.0000000000001952.