Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy

Faculty of Medicine, INSERM U614, 22 Boulevard Gambetta, 76183, Rouen, France.
Human Genetics (Impact Factor: 4.82). 11/2008; 124(5):473-8. DOI: 10.1007/s00439-008-0572-y
Source: PubMed


Biallelic and heterozygous mutations of the BUB1B gene have been reported in mosaic variegated aneuploidy (MVA), a rare disorder characterized by constitutional mosaic aneuploidies associated to severe intrauterine growth retardation, microcephaly and, in most cases, to premature chromatid separation (PCS), highlighting the key role of human BUBR1 in chromosome segregation. To study the consequences of gradual reduction of the BUBR1 protein levels, inhibition of BUB1B expression in model cells was induced using short hairpin RNAs (shRNAs). We obtained stable shRNA-transduced HeLa cells displaying a gradient of residual BUBR1 protein (8.5, 10, 14, 58, and 77%), mimicking the situation of patients' cells harboring one or two BUB1B mutations. Induction of PCS was detected in all transduced cells and its level was correlated to the decrease of BUBR1. Aneuploidy was clearly detected in cells with residual BUBR1 below 50%. Our data demonstrate that the function of the human BUBR1 protein in the spindle checkpoint is remarkably dosage-dependent and that the biological consequences of BUB1B expression reduction on premature chromatid separation and aneuploidy depend on the residual amount of BUBR1. This provides a biological explanation for the mode of inheritance of PCS, which is dominant, and of MVA, which can be recessive in some families and result from the combination of a null allele associated to a common hypomorphic allele in others.

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Available from: jean-michel Flaman, Jun 06, 2014
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    • "Likewise, as mentioned , AT human brains present elevated aneuploidy (Iourov et al., 2009a). Another example of a neurological disorder with excessive aneuploidy is mosaic variegated aneuploidy syndrome (MVA), a disease that can be caused by BUB1B mutations, which leads to impaired mitotic checkpoint and aneuploidy (Bohers et al., 2008; Suijkerbuijk et al., 2010). Identifying chromosomal abnormalities associated with neurological disorders may help locating and predicting genes involved in those complex diseases. "
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