Submission Details

BUBR1 protein encoded by BUB1B gene is an important protein in the spindle assembly checkpoint. Constitutional homozygotes of hypomorphic mutations or compound heterozygote of a null mutation and a missense/hypomorphic mutation in the BUB1B gene cause the rare human disorder mosaic variegated aneuploidy (MVA) syndrome type I (MIM 257300). Hanks S et al., (2004) identified 6 individuals from 5 unrelated families with typical phenotypes of MVA carry biallelic BUB1B mutations. Rio Frio T et al. (2010) identified a male of 34 yr-old from a consanguineous family with MVA phenotype and many types of cancers homozygous for BUB1B 2386-11A>G mutation. Ochiai H et al., (2004) found a Japanese infant with MVA homozygous for mutation ss802470619,NC_000015.10:g.40117088G>A (GRCh38), which is the second allele to the seven individuals who had one allele previously identified (Matsuura S, et al. (2006)). This mutation is a hypomorphic mutation that down regulate the expression of BUB1B gene. Using human HeLa cells Bohers et al. (2008) showed the levels of PCS (premature chromatid separation) and aneuploidy were correlated to the decrease of BUB1B expression. BubR1−/− embryos present mosaicism with a significant percentage of aneuploid cells and premature chromatic separation, growth retardation and marked developmental abnormalities. Progressive apoptosis and reduced cell proliferation finally lead to severe morphological malformation and embryonic death (Schmid M et al., 2014.). More evidence is available in literatures, but the maximum score from genetic evidence and experimental evidences has been reached. In summary, BUB1B gene is definitively associated with mosaic variegated aneuploidy syndrome 1. Variants in this gene have been independently and replicably identified in many individuals with MVA.