title: Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human.
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.
authors: Department of Human Genetics, Biocenter, University of Würzburg, 97074, Würzburg, Germany.
authors: Michael
authors: M
authors: Schmid
authors: Claus
authors: C
authors: Steinlein
authors: Qi
authors: Q
authors: Tian
authors: Amy E
authors: AE
authors: Hanlon Newell
authors: Manfred
authors: M
authors: Gessler
authors: Susan B
authors: SB
authors: Olson
authors: Andreas
authors: A
authors: Rosenwald
authors: Burkhard
authors: B
authors: Kneitz
authors: Lev M
authors: LM
authors: Fedorov
mesh_terms: D000782:Aneuploidy; D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D002871:Chromosome Banding; D020964:Embryo Loss / Q000235:genetics*; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000473:pathology; D005260:Female; D018390:Gene Targeting; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009030:Mosaicism / Q000196:embryology*; D010641:Phenotype; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D032681:Spectral Karyotyping
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases