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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 3  |  Page : 161-170

Roles of Meiotic Defects in Pathogenesis of Primary Ovarian Insufficiency


1 Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
2 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China
3 Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032, China

Date of Submission01-Jul-2017
Date of Web Publication29-Jan-2018

Correspondence Address:
Cong-Jian Xu
Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.224209

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  Abstract 


A matured oocyte has experienced three critical division stages: (1) proliferation in early fetal stage, (2) meiotic arrest at diplotene of prophase I, and (3) meiotic resumption and extrusion of the first polar body. The abnormalities of these stages are associated closely with female reproduction problems including primary ovarian insufficiency (POI), the pathogenic mechanisms of which consist of insufficient initial follicle number, accelerated follicle loss, and arrest of follicle development. Recently, many meiotic associated genetic factors were identified to be mutated in POI patients and mouse models, revealing the association between meiosis and ovarian reserve. In this review, we provide an overview of the genetic factors involved in meiotic prophase I and their pathogenic mechanisms in POI.

Keywords: Genetic Factors; Genotype–Phenotype Correlation; Meiosis; Ovarian Reserve; Primary Ovarian Insufficiency


How to cite this article:
Zhang L, Wang QQ, Tao CQ, Xu CJ. Roles of Meiotic Defects in Pathogenesis of Primary Ovarian Insufficiency. Reprod Dev Med 2017;1:161-70

How to cite this URL:
Zhang L, Wang QQ, Tao CQ, Xu CJ. Roles of Meiotic Defects in Pathogenesis of Primary Ovarian Insufficiency. Reprod Dev Med [serial online] 2017 [cited 2021 Sep 17];1:161-70. Available from: https://www.repdevmed.org/text.asp?2017/1/3/161/224209




  Introduction Top


Primary ovarian insufficiency (POI) is one of the causes for female infertility. The clinical diagnosis of POI is based on the presence of amenorrhea for above 4 months in women younger than 40 years with increased gonadotropin levels, particularly follicle-stimulating hormone, and a decreased estradiol level.[1] POI affects about 1% of the women between the ages of 30 and 40 years, 0.1% of those under 30 years, and 0.01% of those under 20 years.[2] Genetic variants, autoimmune diseases, iatrogenesis, and other abnormalities are considered as the pathogenesis leading to POI. However, only a small proportion of POI patients can be diagnosed with clear pathogenesis.[3],[4] In this review, we focused on the genetic factors which have been reported to be POI causal genes or to be associated with ovarian reserve in mouse models.

The germ cells initiate meiotic division at 11–12 weeks postfertilization in women and 12.5 days postcoitus (dpc) in mice.[5],[6] There are some meiotic-specific events happening in the germ cells including homologous pairing, homologous recombination, and synapsis. Many functional genetic factors in meiosis have been reported to be responsible for maintaining the number of the germ cells and the primordial follicles. It will lead to female infertility or subfertility by loss-of-function mutations in women and mouse models. Besides reproduction problems, the mutations of some meiotic-associated genetic factors also lead to other complex phenotypes such as Fanconi anemia (FA).


  Meiotic Prophase I and the Involved Genetic Factors Top


During meiotic prophase I, chromosomal organization consists of leptonema, zygonema, pachynema, and diplonema. Meiosis starts with the homologous pairing, followed by double-strand breaks (DSBs) formation at leptonema. During zygonema, homologous chromosomal axes are synapsed at DSB repair sites by the recruitment of synaptonemal complex (SC) proteins. The resolution of recombination intermediates happens in the pachynema to form crossovers and noncrossovers. The meiotic division is then arrested at diplonema with chiasmata between nonsister chromatids in the human oocyte. During each stage, many genetic factors were involved as [Figure 1]a shows. The inappropriate formation and repairing of DSBs had significantly blocked the synapsis and recombination, resulting in meiotic errors. Inappropriate meiosis can lead to oocyte loss and ovarian reserve reduction in women and mouse models as [Table 1] shows.
Figure 1: Genetic factors involved in mammalian meiotic prophase I. (a) Meiotic prophase I included DNA DSB formation, end processing, synapsis, strand invasion, strand elongation, crossover formation, and resolution. (b) Synaptonemal complex includes LE, CE, and the TFs connecting the LE and CE. DSB: Double-strand break; LE: Lateral element; CE: Central element; TFs: Transverse filaments.

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Table 1: Roles of meiotic prophase I associated genetic factors in female fertility

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  Role of Double-Strand Break Formation Factors in Mammalian Oogenesis and Primary Ovarian Insufficiency Pathogenesis Top


Pre-DSBs homolog pairing requires the movement of telomere by attachment to the nuclear envelope based on the telomere tethering protein SUN1. Ding et al. found that, in the Sun1-/- oocytes, telomere attachment to the nuclear envelope was disrupted, resulting in much smaller ovaries and completely absent of follicles in adult female mice.[7] During leptonema, SPO11 protein catalyzes the DNA cleavage to form DSBs.[8] Smagulova et al. reported a premature cessation of fertility phenotype in a homozygous female mouse with a modified upstream of the start codon of Spo11 gene (Spo11Gal/Gal).[9] Romanienko and Camerini-Otero reported that Spo11 null mutation caused infertility in adult female mice.[10] In the mutant fetal ovaries at 15 dpc, the number of zygotene cells were reduced, and that of follicles declined sharply in the mutant pubertal mice. The number of DSBs was reduced, and the homologous chromosome synapsis in Spo11Gal/Gal mice is incomplete. Ovaries in Spo11Gal/Gal were smaller than that in wild type and showed greatly diminished number of follicles. Young female mice were fertile, but no viable litters were obtained older than 6 months. In the mice with more deleterious genotype of Spo11Gal/-, the ovary showed a further reduction in size and no visible follicles.

POF1B was putative to function in meiotic chromosome pairing.[11] Bione et al. identified balanced translocations disrupting the POF1B in premature ovarian failure (POF) patients.[12] Lacombe et al. also identified homozygous point mutation in exon 10 of the POF1B gene in 5 affected sisters from a Lebanese family with POF.[11] However, it lacks deep study in mouse model to demonstrate the molecular mechanism in meiosis.

In mammals, MEI1 is likely to be the functional homolog of Arabidopsis thaliana putative recombination initiation defect 1 (AtPRD1). AtPRD1 is required for meiotic DSBs formation and involved in chromosomal recombination.[13] As Munroe et al. had reported, null mutation of Mei1 in female mice lead to infertility with depleted ovaries and lack of oocytes.[14] In the homozygous mutant (mei1/mei1) ovaries, Libby et al. observed the defects in meiosis and aberrant first meiotic divisions, with a defect in DSBs formation and synapsis.[15] Kumar et al. reported that MEI4 could be a limiting factor for DSB formation, and the localization of MEI4 protein also required other important factors such as MEI1, REC8, and RAD21L in mouse.[16] Furthermore, the disrupted association of MEI4 with chromosome axis upon DSB repairment contributes to the turning off of meiotic DSB formation, resulting in few primordial and primary follicles in ovaries of 2 weeks old and complete absence of follicles at 8 weeks old. HOMAD1 is predicted to promote homolog alignment and assembly of the SC in mouse. In mammalian germ cells, a conserved multiprotein complex of MRE11, RAD50, and NBS1 is important for DSB repair, meiotic recombination, and telomere maintenance.[17] In the mouse models containing an A to T change at nucleotide 1894 of the coding sequence of Mre11, Theunissen et al. found that the female mice exhibited dramatically reduced fertility; however, the follicular development was not affected.[18]Rad50 mutant mouse exhibited ovarian atrophy with significantly reduced follicle number, as Roset et al. reported.[19]NBS1, a causal gene of Nijmegen breakage syndrome (NBS), is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. In addition, POF observed in NBS patients also supports the notion that it may be involved in meiotic recombination.[20] As Kang et al. reported, disruption of mouse Nbs1 by target replacing exons 2 and 3 (resulted in a frameshift splicing between exon 1 and exon 4) leads to highly degenerated ovaries and completely lack of oocytes and follicles in the ovaries.[21] Furthermore, by conditional knock out of Nbs1 in the ovary, 50% of the female mice showed a reduction of ovary size and oocyte number.[22]


  Roles of Synaptonemal Complexes in Mammalian Oogenesis and Primary Ovarian Insufficiency Pathogenesis Top


Synapsis is an essential event to ensure proper chromosome segregation during anaphase of the first meiotic division.[23] In most meiotic systems, the paired homologous chromosomes are connected by SC, a protein lattice that resembles railroad tracks. The SC included three structures as [Figure 1]b shows: lateral elements (LEs) on two side rails, central element (CE), and the transverse filaments (TFs) connecting the LE and CE. The mammalian LEs include two components: SYCP2 and SYCP3. Four proteins, SYCE1, SYCE2, SYCE3, and TEX12, have been identified in CE. SYCP1 is the single constituent of TF. All the seven mammalian SC components are meiosis specific.[24] The defective SCs were tightly associated with oogenesis and fertility in women and mouse models as [Table 1] shows. Bolor et al. reported a SYCP3 splicing donor region mutation and a missense mutation in 2 of 26 women with recurrent pregnancy loss of unknown cause.[25] Both mutations were found to affect the splicing and result in abnormal transcript. The experiment in vitro to analyze the functions of mutant SYCP3 showed that both mutant proteins had lost the normal properties to form a thick fiber in a loop-like structure in the nucleus as observed in the wild-type control cells. De Vries et al. had identified SYCE1 mutations in POI patient's sisters.[26] In the affected sisters, a nonsense homozygous mutation (c.613C > T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation, which was not identified in the DNA samples from the 90 controls.

STAG3 is essential for the formation of SC in mice and humans as Pezzi et al. reported.[27] Caburet et al. identified homozygosis of a 1-bp deletion in the STAG3 gene in a large consanguineous Palestinian family with POF.[28] STAG3 truncating variant, splice-site mutation, and missense mutation were identified recently in POF patients.[29],[30],[31]


  Roles of Strand Invasion and Double-Strand Break Repairing Factors in Mammalian Oogenesis and Primary Ovarian Insufficiency Pathogenesis Top


During meiotic prophase I, chromosomes must undergo highly regulated recombination events, in which RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and SCs.[32] Human RAD51 and DMC1 proteins were reported to exhibit DNA-dependent ATPase activity and possess the ability to promote homologous pairing and strand transfer reactions in vitro.[33] These characteristics indicate significant functional similarities of the two proteins. Mice heterozygous for Rad51 null mutation were viable and fertile, but in the homozygous state, the mutation resulted in a defective preimplantation, as Tsuzuki et al. reported.[34] Yoshida et al. found that, in the female mouse lacking Dmc1, normal differentiation of oogenesis was aborted in embryos and germ cells disappeared in adult mouse ovary.[35] In the Dmc1-deficient mice, ovaries were greatly reduced in size at 8-week postnatal compared with the ovaries of wild-type female mice of the same age. Meanwhile, the adult ovaries from the mutant females had no follicles at any developmental stage. Yoshida et al. also observed leptotene, zygotene, and pachytene oocytes in meiosis in the genital ridges of 16 dpc in the Dmc1-deficient mouse embryos. However, there were only follicle cells and small apoptotic cells with no germ cells in the mutant ovary from mice just after birth. In the mutant mice, neither pachytene nor diplotene chromosomes were detected.

The HOP2 and MND1 proteins from human and mouse are associated to form a stable heterodimeric complex which stimulates the recombinase activity of RAD51 and DMC1.[36],[37] Their disruption results in severe defects in recombination and homologous chromosome synapsis, leading to ovarian dysfunction. Zangen et al. identified a homozygous in-frame 3-bp deletion in HOP2 gene from affected members in a large consanguineous Arab Palestinian pedigree with hypergonadotropic ovarian dysgenesis.[38] The patients were infertile and showed primary amenorrhea, uterine hypoplasia, and undetectable ovaries by abdominal ultrasound and magnetic resonance imaging. Petukhova et al. found that Hop2 knockout mice showed no follicles in the ovary and greatly reduced ovary size.[39] Pezza et al. found reduction in ovary size and the absence of follicles and corpora lutea in Mnd1 homozygous knockout mice.[40] BRIT1 was also involved in mitotic and meiotic recombination DNA repair by mediating recruitment of RAD51/BRCA2 to the damaged site and maintaining genomic stability in mice as Liang et al. reported.[41] The null mutation of Brit1 resulted in female infertility with much smaller ovary with no follicles. On the other hand, RAD54 protein dissociates RAD51 from nucleoprotein filaments formed on double-stranded DNA.[42]In vitro, RAD54 had been shown to stimulate DNA pairing of RAD51, a key homologous recombination protein, as Bugreev et al. reported.[43] Loss of RAD54 affects trophoblastic development and the pattern of X-inactivation in extraembryonic tissues.[44]

MEIOB encodes a chromatin-associated protein that is required for meiotic recombination and synapsis by forming a complex with RPA1 and SPATA22.[45],[46] These three proteins colocalize in foci that are associated with meiotic chromosomes. MEIOB binds to single-stranded DNA and exhibits 3'-5' exonuclease activity. The mouse ovaries are strongly reduced in size and progressively lose oocytes in Meiob homologous mutated ovaries.[45],[46] Furthermore, mice with Spata22 homozygous mutation presented with small ovaries, which lacked oocytes and contained degenerated follicles.[47]

MSH4, MSH5, BLM, TEX11, and RNF212 show partial colocalization with recombination foci (defined by RAD51 and DMC1) on synapsed axes. These proteins appear at zygonema and are predicted to play a part in stabilizing and/or processing recombination intermediates. MSH4 belongs to the DNA mismatch repair (MMR) family of proteins, which have been linked to postreplicative MMR and is involved in meiotic recombination. The human MSH4 protein physically interacts with both RAD51 and DMC1 to initiate DNA strand exchange between homologous chromosomes.[48] A homozygous donor splice-site mutation in human MSH4 causes POI, as Carlosama et al. had reported.[49] The affected patients came from a pedigree. The mutation was located on a splicing donor site (c.2355+1G>A), resulting in two possible abnormal translation products, exon skipping and truncated protein. The skipped exon included 43 amino acids in a highly conserved Walker B motif of the ATP-binding domain of MSH4, which probably impaired the functionality of MSH4–MSH5 dimer severely, resulting in meiotic failure. Guo et al. reported a homozygous missense mutation in the MSH5 gene in two Chinese sisters with POF.[50] The Msh4 null mutant (Msh4-/-) female mice, as Kneitz et al. reported, showed meiotic failure and infertility.[51] The earliest ovarian phenotype in Msh4-/- oocyte can be detected at 2-day postnatal, at which time many oogonia had been lost. Msh4-/- females had very small ovaries containing few oocytes at 4 weeks old. The Msh5-/- mice were also infertile. The ovary size was markedly reduced and no developing follicles can be found in the homozygous mutant ovaries at 2 months of age, and no germ cells were observed.[50] The mammalian Msh4 was reported to form heterodimeric complexes with Msh5.[52] By crossing, double-mutant Msh4-/-/Msh5-/- mice were generated and were infertile. The degree of chromosome pairing during meiosis I in Msh4-/-/Msh5-/- mice was similar to that seen in Msh5-/- mice, indicating that mammalian MSH5 functions upstream of MSH4 within the same epistasis group and both MSH4 and MSH5 are required to ensure proper chromosome synapsis.[51]

Reynolds et al. found that RNF212 was required to stabilize MSH4 and TEX11.[53] The Rnf212-/- mutant female mice were sterile, with normal ovary size and large number of oocytes in mature animals. Complete synapsis is achieved in Rnf212 knockout mice; however, crossing-over is diminished in the absence of RNF212. Kong et al. identified two single-nucleotide polymorphisms which were associated with genome-wide recombination rate.[54] Yang et al. identified that Tex11 was the first X-encoded meiosis-specific factor in mice.[55] TEX11 forms discrete foci on synapsed regions of meiotic chromosomes and interacts with SYCP2, an integral component of the SC LEs. In Tex11-deficient female mice, chromosomal synapsis and crossover formation were reduced. The Tex11-/- females were fertile and produced offspring but displayed a reduction in litter size.

The MCM8–MCM9 complex promotes RAD51 recruitment at DNA damaged sites to facilitate homologous recombination.[56],[57] AlAsiri et al. reported an MCM8 gene missense mutation in 3 Saudi Arabian sisters with hypergonadotropic primary amenorrhea.[58] This mutation was proved to decrease the DNA-binding affinity of MCM8 and deficiency of DSBs repair. Tenenbaum-Rakover et al. also identified homozygous mutations (a splice-site mutation in the first family and a 2-bp insertion in another family) of MCM8 gene in patients with primary gonadal failure characterized by primary amenorrhea or early menopause in females.[59] Wood-Trageser et al. identified homozygosis for a splice-site mutation and a nonsense mutation of the MCM9 gene in ovarian digenesis patients from two unrelated families.[60] Fauchereau et al. identified a homozygosis for a nonsense mutation of the MCM9 gene in sister patients with POI.[61] Both Mcm8-/- and Mcm9-/- female mice were sterile and the ovaries were completely devoid of oocytes.[56]

RecQ helicases play a central role in maintaining genome stability and may interact with some important cancer-related proteins such as BRCA1, also known as FANCS. RecQL3 (also known as BLM) is a causal gene of Bloom syndrome. The BLM protein has been shown to localize at SCs in mouse spermatocytes.[62] Women with Bloom syndrome generally have reduced fertility and experience menopause at an earlier age than usual.[63] TOP3A and BLM were shown to colocalize on lateral and some axial elements of human spermatocytes.[64] In mice, BLM and TOP3a mRNAs are highly expressed in testis.[65]

HEI10 is essential for the crossover/noncrossover differentiation process during mammalian recombination.[66] Normally, HEI10 accumulates at designated crossover sites and stabilizes the recombination factors at crossover and noncrossover sites. Disruption of HEI10 interferes meiotic crossing-over.[67]HFM1, expressed exclusively in ovary and testis, is encoding human DNA helicases, functioning in genome integrity, and is essential for meiotic homologous recombination and proper synapsis between homologous chromosomes.[68] Guiraldelli et al. reported that the null mutation of mouse Hfm1 gene resulted in female infertility with small ovaries, increased numbers of stromal cells, and fewer follicle and corpora lutea.[69]HFM1 compound heterozygous mutations were found in a small fraction of POI patients, reported by Wang et al.[70]CPEB1 was also deemed to regulate the SCs formation progress and its null mutation resulted in vestigial ovaries that were devoid of oocytes in adult female mice.[71] The heterozygous copy number deletion in human chromosomal 15q25.2 disrupted CPEB1 gene caused POI phenotypes in three unrelated patients, as Hyon et al. reported.[72] All the three patients showed small size of ovary and fewer or none follicles in the ovary. CPEB1 is a sequence-specific RNA binding protein, which binds the cytoplasmic polyadenylation element (CPE) to regulate translation during vertebrate oocyte maturation.


  Roles of Fa Genes in Meiotic Double-Strand Break Reparing and Female Fertility Top


The FA genes were reported to be implicated in a common pathway which is important for the repair of DNA inter-strand crosslink lesions, covalently linking two strands of DNA together.[73] The reported FA genes are listed in [Table 2] from the review by Wang and Smogorzewska.[74] Only a few FA genes were proved to be essential for meiosis with deep molecular mechanism study. There is a high frequency of reproduction system defects based on MGI database, as [Table 2] shows. Among 26 FA genes, 20 of them had corresponding null alleles and mice strings. Ovary phenotypes were available in 13 mice strings and were not available in the rest. To our surprise, 12 of 13 mice strings were proved to manifest POI-like phenotype, including small ovary, decreased oocyte number, absence of ovarian follicles, reduced female fertility, and decreased litter size. It suggested that some of the DSB repairing mechanisms were shared by germ cells and somatic cells, and the systematic phenotypes including hematological system and reproduction system can be caused by the same involved genetic factors.
Table 2: Roles of FA genes in oogenesis and human/mouse fertility

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  Roles of Crossover Resolution Factors in Mammalian Oogenesis and Primary Ovarian Insufficiency Pathogenesis Top


The crossovers and noncrossovers are generated at the end of pachytene, and crossovers were regulated by MLH1, MLH3, and EXO1. MLH1 is a marker of crossover sites. Mlh1 was required for the formation of most (90%–95%) crossovers, but not noncrossovers.[98] The Mlh1 mutant mice manifested sterility, both female and male mice, with high levels of prematurely separated chromosomes in spermatocytes which arrest in the first meiotic division.[99]MLH1 mutations were found in hereditary nonpolyposis colorectal cancer patient; however, no POI patients were reported to carry MLH1 mutation. MLH3 is required for MLH1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid-pachynema stage of prophase I.[100] MLH3 protein (two isoforms) interacts with the human MSH4 protein in vitro, suggesting that MLH3 is associated with MSH4 in mammalian meiotic recombination.[101] The Mlh3-/- female mice were also sterile. EXO1 has 5-prime-to-3-prime polarity of exonuclease activity and participated in mismatch-provoked excision directed by strand breaks.[102] Wei et al. reported that MLH3 was needed for the exonuclease activity when the break was located 3-prime to the mispairing.[103] Homozygous Exo1-null mutant female mice were infertile because of meiotic failure and apoptosis of the oocyte.


  Conclusions Top


We have reviewed the genetic factors in meiosis prophase I, elucidated the association between meiosis defects and oogenesis in women and mouse models and demonstrated a significant role of meiotic defects in ovarian reserve reduction and POI pathogenesis.

Financial support and sponsorship

This work was supported by funding from the National Key R&D Program of China (2016YFC1303100). We would like to thank Professor Feng Zhang for his critical comments.

Conflicts of interest

There are no conflicts of interest.



 
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