Abstract
Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions. To develop our hypothesis, we modeled this process in the mouse after inactivation of protein BubR1, one of the key players of SAC. We found that soon after implantation, more than 50 % of cells of BubR1 -/- embryos were aneuploid and had an increased level of premature sister chromatid separation (PSCS). Aneuploid cells do not have a predominant gain or loss of some specific chromosomes, but they have mosaic variegated aneuploidy (MVA), which is characterised by random mixture of different chromosomes. MVA leads to growth retardation, stochastic massive apoptosis, disruption of bilateral symmetry, and embryo death between embryonic days 7.5 to 13.5. Analysis published human data revealed that human recurrent pregnancy loss (RPL) embryos and rare infant patients carrying BubR1 mutations that have been described so far have the PSCS and MVA as in BubR1 deficient/insufficient mice. Based on this data, we predict that deficiency/insufficiency of BubR1 and other components of the SAC in human are responsible for a significant fraction of both early and late RPLs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 375-392 |
| Number of pages | 18 |
| Journal | Chromosome Research |
| Volume | 22 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- BubR1 deficiency
- Mosaic variegated aneuploidy
- Pregnancy loss
- Spindle assembly checkpoint
ASJC Scopus subject areas
- Genetics
- Medicine(all)
Cite this
Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human. / Schmid, Michael; Steinlein, Claus; Tian, Qi; Hanlon Newell, Amy E.; Gessler, Manfred; Olson, Susan; Rosenwald, Andreas; Kneitz, Burkhard; Fedorov, Lev.
In: Chromosome Research, Vol. 22, No. 3, 2014, p. 375-392.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human
AU - Schmid, Michael
AU - Steinlein, Claus
AU - Tian, Qi
AU - Hanlon Newell, Amy E.
AU - Gessler, Manfred
AU - Olson, Susan
AU - Rosenwald, Andreas
AU - Kneitz, Burkhard
AU - Fedorov, Lev
PY - 2014
Y1 - 2014
N2 - Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions. To develop our hypothesis, we modeled this process in the mouse after inactivation of protein BubR1, one of the key players of SAC. We found that soon after implantation, more than 50 % of cells of BubR1 -/- embryos were aneuploid and had an increased level of premature sister chromatid separation (PSCS). Aneuploid cells do not have a predominant gain or loss of some specific chromosomes, but they have mosaic variegated aneuploidy (MVA), which is characterised by random mixture of different chromosomes. MVA leads to growth retardation, stochastic massive apoptosis, disruption of bilateral symmetry, and embryo death between embryonic days 7.5 to 13.5. Analysis published human data revealed that human recurrent pregnancy loss (RPL) embryos and rare infant patients carrying BubR1 mutations that have been described so far have the PSCS and MVA as in BubR1 deficient/insufficient mice. Based on this data, we predict that deficiency/insufficiency of BubR1 and other components of the SAC in human are responsible for a significant fraction of both early and late RPLs.
AB - Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions. To develop our hypothesis, we modeled this process in the mouse after inactivation of protein BubR1, one of the key players of SAC. We found that soon after implantation, more than 50 % of cells of BubR1 -/- embryos were aneuploid and had an increased level of premature sister chromatid separation (PSCS). Aneuploid cells do not have a predominant gain or loss of some specific chromosomes, but they have mosaic variegated aneuploidy (MVA), which is characterised by random mixture of different chromosomes. MVA leads to growth retardation, stochastic massive apoptosis, disruption of bilateral symmetry, and embryo death between embryonic days 7.5 to 13.5. Analysis published human data revealed that human recurrent pregnancy loss (RPL) embryos and rare infant patients carrying BubR1 mutations that have been described so far have the PSCS and MVA as in BubR1 deficient/insufficient mice. Based on this data, we predict that deficiency/insufficiency of BubR1 and other components of the SAC in human are responsible for a significant fraction of both early and late RPLs.
KW - BubR1 deficiency
KW - Mosaic variegated aneuploidy
KW - Pregnancy loss
KW - Spindle assembly checkpoint
UR - http://www.scopus.com/inward/record.url?scp=84906066935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906066935&partnerID=8YFLogxK
U2 - 10.1007/s10577-014-9432-x
DO - 10.1007/s10577-014-9432-x
M3 - Article
C2 - 24981203
AN - SCOPUS:84906066935
VL - 22
SP - 375
EP - 392
JO - Chromosome Research
JF - Chromosome Research
SN - 0967-3849
IS - 3
ER -