Maternal age and trisomy – a unifying mechanism of formation

Wolstenholme, John; Angell, RR

doi:10.1007/s004120100142

Cited by 20 publications

(21 citation statements)

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“…In addition to the non-disjunction theory, Angell et al have postulated the existence of a different mechanism for the occurrence of aneuploidy [130]. According to their finding, premature separation of chromatids during meiosis might be the main factor contributing to the formation of oocytes with abnormal chromosomal complements.…”

Section: Menopausementioning

confidence: 99%

Reproductive ageing in women

Djahanbakhch

Ezzati

Zosmer

2007

The Journal of Pathology

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The traditional view in respect to female reproduction is that the number of oocytes at birth is fixed and continuously declines towards the point when no more oocytes are available after menopause. In this review we briefly discuss the embryonic development of female germ cells and ovarian follicles. The ontogeny of the hypothalamic-pituitary-gonadal axis is then discussed, with a focus on pubertal transition and normal ovulatory menstrual cycles during female adult life. Biochemical markers of menopausal transition are briefly examined. We also examine the effects of age on female fertility, the contribution of chromosomal abnormalities of the oocyte to the observed decline in female fertility with age and the possible biological basis for the occurrence of such abnormalities. Finally, we consider the effects of maternal age on obstetric complications and perinatal outcome. New data that have the potential to revolutionize our understanding of mammalian oogenesis and follicular formation, and of the female reproductive ageing process, are also briefly considered.

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Section: Menopausementioning

confidence: 99%

Reproductive ageing in women

Djahanbakhch

Ezzati

Zosmer

2007

The Journal of Pathology

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“…57 It is not only age-dependent factors that play a role in the production of aneuploid oocytes; an individual predisposition originating during early meiotic stages could also be very important. Synaptic errors between homologous chromosomes, 58 a reduction in the number of chiasmata because of a low recombination rate 59 and the subsequent segregation of these unstable bivalents, 60 an altered DNA repair because of defects in sister chromatid cohesion 61 and other mechanisms are being found to play an important role. Alterations in meiosis-specific proteins involved in the maintenance of the cohesion of sister chromatids 55 and mutations in genes required for chiasma formation and for the structural integrity of meiotic bivalents 62 have been related to aneuploidy.…”

Section: Aneuploidy Ratementioning

confidence: 99%

Analysis of nine chromosome probes in first polar bodies and metaphase II oocytes for the detection of aneuploidies

et al. 2003

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We used fluorescent in situ hybridisation (FISH) to detect nine chromosomes (1,13,15,16,17,18,21,22 and X) in 89 first Polar Bodies (1PBs), from in vitro matured oocytes discarded from IVF cycles. In 54 1PBs, we also analysed the corresponding oocyte in metaphase II (MII) to confirm the results; the other 35 1PBs were analysed alone as when preimplantation genetic diagnosis using 1PB (PGD-1PB) is performed. The frequency of aneuploid oocytes found was 47.5%; if the risk of aneuploidy for 23 chromosomes is estimated, the percentage rises to 57.2%. Missing chromosomes or chromatids found in 1PBs of 1PB/MII doublets were confirmed by MII results in 74.2%, indicating that only 25.8% of them were artefactual. Abnormalities observed in 1PBs were 55.8% whole-chromosome alterations and 44.2% chromatid anomalies. We observed a balanced predivision of chromatids for all chromosomes analysed. Differences between balanced predivision in 1PB and MII were statistically significant (Po0.0001, v 2 test); the 1PB was most affected. The mean abnormal segregation frequency for each chromosome was 0.89% (range 0.52-1.70%); so, each of the 23 chromosomes of an oocyte has a risk of 0.89% to be involved in aneuploidy. No significant differences were observed regarding age, type of abnormality (chromosome or chromatid alterations) or frequency of aneuploidy. Nine of the 35 patients (25.7%) whose 1PB and MII were studied presented abnormalities (extra chromosomes) that probably originated in early oogenesis. Analysis of 1PBs to select euploid oocytes could help patients of advanced age undergoing in vitro fertilization (IVF) treatment.

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“…It causes genetic imbalances that may transform cells and lead to cancer development in somatic tissues. In germ lines, missegregation in either meiosis I, mainly manifested as nondisjunction of homologue chromosomes, or meiosis II, manifested as premature sister chromatid separation, will generate aneuploid gametes, directly affecting the fecundity of an organism (26,37). Although the molecular mechanisms underlying chromosome segregation errors in meiosis are still not clear (6), deregulation of separase, either directly or indirectly, is likely a significant contributor.…”

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confidence: 99%

Preimplantation Mouse Embryos Depend on Inhibitory Phosphorylation of Separase To Prevent Chromosome Missegregation

Huang

Andreu-Vieyra

Wang

et al. 2009

Molecular and Cellular Biology

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Separase is a critical protease that catalyzes the cleavage of sister chromatid cohesins to allow the separation of sister chromatids in the anaphase. Its activity must be inhibited prior to the onset of the anaphase. Two inhibitory mechanisms exist in vertebrates that block the protease activity. One mechanism is through binding and inhibition by securin, and another is phosphorylation on Ser1126 (in humans [Ser1121 in mice]). These two mechanisms are largely redundant. However, phosphorylation on Ser1121 is critical for the prevention of premature sister separation in embryonic germ cells. As a result, Ser1121-to-Ala mutation leads to depletion of germ cells in development and subsequently to infertility in mice. Here, we report that the same mutation also causes embryogenesis failure between the 8-and 16-cell stages in mice. Our results indicate a critical role of separase phosphorylation in germ cell development as well as in early embryogenesis. Thus, deregulation of separase may be a significant contributor to infertility in humans.Sister chromatids are held together by a multisubunit complex called cohesin composed of . To separate the sister chromosomes, cohesin complexes are removed in a two-step process. First, cohesins on chromosome arms are removed by Plk1-and Aurora B-mediated phosphorylation before the anaphase (4,8,19,20,31,35). Second, the centromere-localized cohesins, which are protected by Sgo and PP2A from phosphorylation-mediated removal (13,21,28,29,32), are cleaved by a protease called separase at the onset of the anaphase (33, 34). Prior to the anaphase, separase is inhibited by securin and by phosphorylation, which is most likely catalyzed by cyclin B1/Cdk1. phosphorylation by cyclin B1/Cdk1 per se is not inhibitory to separase. Rather, the phosphorylation allows the binding of cyclin B1/Cdk1 as an inhibitor to separase (5). Two phosphorylation sites in separase, Ser1126 and Thr1326 (Ser1121 and Thr1321 in mice, respectively), that are important for the inhibition have been identified (30). Activation of separase depends on the function of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), since both securin and cyclin B1 are substrates of APC/C (1-3, 15,16,23,25,27,36). Given that APC/C is inhibited by the spindle assembly checkpoint, separation of sister chromatids therefore cannot occur until the checkpoint is satisfied. Thus, the spindle assembly checkpoint prevents premature sister separation and ensures chromosomal stability.Missegregation of chromosomes has dire consequences. It causes genetic imbalances that may transform cells and lead to cancer development in somatic tissues. In germ lines, missegregation in either meiosis I, mainly manifested as nondisjunction of homologue chromosomes, or meiosis II, manifested as premature sister chromatid separation, will generate aneuploid gametes, directly affecting the fecundity of an organism (26,37). Although the molecular mechanisms underlying chromosome segregation errors in meiosis are still not clear (6), deregula...

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Maternal age and trisomy – a unifying mechanism of formation

Cited by 20 publications

References 0 publications

Reproductive ageing in women

Reproductive ageing in women

Analysis of nine chromosome probes in first polar bodies and metaphase II oocytes for the detection of aneuploidies

Preimplantation Mouse Embryos Depend on Inhibitory Phosphorylation of Separase To Prevent Chromosome Missegregation

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