title: Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice.
abstract: Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here, we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice and that the effect increases with advancing maternal age. Analysis of Bub1 heterozygous oocytes showed that aneuploidy occurred primarily during the first meiotic division and involved premature sister chromatid separation. Furthermore, aneuploidy was inherited in zygotes and resulted in the loss of embryos after implantation. The incidence of aneuploidy in zygotes was sufficient to explain the reduced litter size in matings with Bub1 heterozygous females. No effects were seen in germ cells from heterozygous males. These findings show that Bub1 dysfunction is linked to inherited aneuploidy in female germ cells and may contribute to the maternal age-related increase in aneuploidy and pregnancy loss.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Leland
authors.forename: Prabakaran
authors.initials: P
authors.lastname: Nagarajan
authors.forename: Aris
authors.initials: A
authors.lastname: Polyzos
authors.forename: Sharon
authors.initials: S
authors.lastname: Thomas
authors.forename: George
authors.initials: G
authors.lastname: Samaan
authors.forename: Robert
authors.initials: R
authors.lastname: Donnell
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.forename: Sundaresan
authors.initials: S
authors.lastname: Venkatachalam
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002503:Centromere / Q000502:physiology; D005260:Female; D005298:Fertility; D006579:Heterozygote; D008098:Litter Size; D008297:Male; D008423:Maternal Age; D008540:Meiosis; D051379:Mice; D009154:Mutation; D009865:Oocytes / Q000648:ultrastructure*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D012333:RNA, Messenger; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases