Reduced expression of Mad2 and Bub1 proteins is associated with spontaneous miscarriages.

During early development of the human embryo, chromosomal imbalance and instability may cause spontaneous miscarriages. In this study, we observe aberrant chromosome numbers in nearly half of spontaneous miscarriage embryo samples, most of which show abnormalities in karotype. We also detect significantly reduced expression of two important mitotic checkpoint proteins, Mad2 and Bub1. To further investigate the role of Bub1 and Mad2 in chromosome mis-segregation, in embryogenesis, and in errors leading to spontaneous miscarriages, we used RNA interference technology to knockdown Bub1 and Mad2 genes. We examined the effect of reduced expression of Mad2 and Bub1 on chromosome number, cell proliferation and cell cycle progression. Significant suppression of cell proliferation and increased abnormal chromosome numbers were detected. M phase arrest was observed in cultured villus cell lines with depleted Mad2 or Bub1 mRNA by RNAi technique. The results from the in vitro RNAi-mediated silencing model may provide an explanation for the observations in clinical samples of spontaneous miscarriages. Thus, our findings strongly suggest that the loss of spindle assembly checkpoint proteins, such as Bub1 and Mad2, may cause spontaneous miscarriages.