Alternative titles; symbols
HGNC Approved Gene Symbol: BUB1B
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38): 15:40,161,069-40,221,123 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.1 | [Premature chromatid separation trait] | 176430 | Autosomal dominant | 3 |
| Colorectal cancer, somatic | 114500 | 3 | ||
| Mosaic variegated aneuploidy syndrome 1 | 257300 | Autosomal recessive | 3 |
The BUB1B gene encodes a protein that plays a critical role in regulating the spindle-assembly checkpoint by means of 3 apparently independent mechanisms: acting as a diffuse inhibitor, facilitating catalysis at the kinetochore, and being required for chromosomal alignment during metaphase (summary by Rio Frio et al., 2010).
To identify human genes that play a role in mitotic checkpoints and chromosome segregation, Cahill et al. (1998) searched an expressed sequence tag database with the yeast and mouse BUB1 (see 602452) sequences and performed RT-PCRs. They isolated human cDNAs encoding BUB1B, which they called BUBR1. The predicted BUB1B protein contains the conserved CD1 and CD2 domains that are found in yeast, human, and mouse BUB1; the human and mouse BUB1B proteins are 29% identical in these regions. CD1 directs kinetochore localization and binding to Bub3, and CD2 contains the kinase domain. Between CD1 and CD2, the BUB1B protein has a putative nuclear localization signal, which is present in human and mouse BUB1 but not in yeast BUB1. Cahill et al. (1998) detected BUB1B gene expression in all 19 colorectal cancer cell lines showing a chromosome instability (CIN) phenotype that they analyzed.
Independently, Taylor et al. (1998) isolated cDNAs encoding BUB1B. They reported that the predicted 1,050-amino acid protein binds BUB3 (603719) via a BUB3-binding domain similar to that found in BUB1.
Davenport et al. (1999) isolated cDNAs encoding the mouse Bub1b homolog. The predicted mouse and human proteins are approximately 75% identical. Sequence analysis revealed that the Bub1b protein contains a putative cyclin destruction box that can target proteins for degradation by proteosomes during mitosis.
By histologic analysis, Simmons et al. (2019) showed that Bubr1 localized on chromosomes and spindles in neural progenitor cells (NPCs) during NPC mitosis in developing mouse cortex. Bubr1 persisted in cytoplasm of cycling cells during interphase.
Lampson and Kapoor (2005) found that depletion of BUB1B by RNA interference resulted in failure of HeLa cells to form stable kinetochore-microtubule attachments. Inhibition of Aurora kinase activity or depletion of Aurora B (604970) stabilized the kinetochore-microtubule attachments in BUB1B-depleted cells. Lampson and Kapoor (2005) concluded that BUB1B links the regulation of chromosome-spindle attachment to mitotic checkpoint signaling.
Using Xenopus egg extracts, Mao et al. (2003) identified bifunctional roles for Bubr1 in the mitotic checkpoint: an enzymatic role that required Cenpe (117143)-dependent activation of Bubr1 kinase activity at kinetochores, and a stoichiometric role as a direct inhibitor of Cdc20 (603618).
Using short hairpin RNAs, Bohers et al. (2008) developed a series of HeLa cells displaying a gradient of residual BUB1B expression. All transduced cells showed premature chromatid separation, and the level of separation correlated inversely with residual BUB1B expression. Aneuploidy was detected in cells with less than 50% residual BUB1B expression. Bohers et al. (2008) concluded that the consequence of reduced BUB1B expression on the spindle checkpoint is dose dependent on residual BUB1B expression.
Homer et al. (2009) found that the spindle assembly checkpoint protein BubR1 regulates both prophase I arrest and prometaphase progression in mouse oocytes. Homer et al. (2009) showed that oocytes depleted of BubR1 cannot sustain prophase I arrest and readily undergo germinal vesicle breakdown, a marker for reentry into meiosis I. BubR1-depleted oocytes then arrest before completing meiosis, marked by failure of polar body extrusion. Both meiotic defects in BubR1-depleted oocytes are due to reduced activity of the master regulator known as the anaphase-promoting complex (APC), brought about through diminished levels of the APC coactivator Cdh1 (192090).
By fluorescence in situ hybridization using a genomic clone, Cahill et al. (1998) mapped the BUB1B gene to chromosome 15q14-q21. Using the same technique, Davenport et al. (1999) refined the map position to chromosome 15q15.
Cancer
In 2 of 19 colorectal cancer cell lines, Cahill et al. (1998) identified somatic mutations in the BUB1B gene. Neither mutation was found among 40 normal alleles. The first mutation was a germline transition at codon 40 (602860.0001); the second mutation was a somatic deletion at codon 1023 (602860.0002). The authors did not determine whether either of these BUB1B mutations functionally alters the gene product.
Premature Chromatid Separation Trait and Mosaic Variegated Aneuploidy Syndrome
Mosaic variegated aneuploidy (MVA; 257300) is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases. Hanks et al. (2004) hypothesized that mutations of a gene involved in the mitotic spindle checkpoint might underlie MVA. In affected members of 5 of 8 MVA families, they identified biallelic mutations in the BUB1B gene (see, e.g., 602860.0003-602860.0010). Each family carried 1 missense mutation and 1 mutation resulting in premature protein termination or an absent transcript. Five of the 6 missense mutations were in the kinase domain and affected residues conserved in BubR1 orthologs in mouse and chicken. Three of the families had previously been reported by Limwongse et al. (1999) and Plaja et al. (2001).
Matsuura et al. (2006) identified heterozygosity for mutations in the BUB1B gene (see, e.g., 602860.0011-602860.0012) in affected members of 7 unrelated Japanese MVA families. Four families had the same truncating mutation (1833delT; 602860.0011). Although a second mutation was not identified in any of the families, 5 of 7 families had a haplotype, referred to as 6G3 (26020GT, 1046GA, D15S994), that was associated with decreased levels of the BUB1B transcript and protein. Western blot analysis showed a trend toward a descending order of BUB1B expression from normal individuals (63 to 158% of control values), those with the 6G3 haplotype (31 to 71%), those with a truncating mutation (21 to 57%), and those with a truncating mutation plus the 6G3 haplotype (22 to 29%). Western blot analysis from 2 patients showed decreased BUB1B expression with normal levels of P55CDC (CDC20; 603618), a protein-specific activator of the anaphase-promoting complex. However, P55CDC did not localize correctly to the kinetochore, indicating abnormal mitotic spindle checkpoint signaling. Matsuura et al. (2006) concluded that allelic variation of BUB1B gene expression conferred by the 6G3 haplotype could explain the apparent discrepancy between the finding of biallelic mutations in MVA and monoallelic mutations in the PCS trait (176430). The authors concluded that a greater than 50% decrease in BUB1B activity results in abnormal mitotic spindle checkpoint function and MVA syndrome.
Wang et al. (2004) examined the physiologic function of BUBR1, a key component of the spindle checkpoint, by generating Bubr1 mutant mice. Bubr1 -/- embryos failed to survive beyond day 8.5 in utero as a result of extensive apoptosis. Whereas Bubr1 +/- blastocysts grew relatively normally in vitro, the Bubr1 -/- blastocysts exhibited impaired proliferation and atrophied. Adult Bubr1 +/- mice manifested splenomegaly and abnormal megakaryopoiesis. Heterozygous (haploinsufficient) mice showed an increase in the number of splenic megakaryocytes, which was correlated with an increase in megakaryocytic, but a decrease in erythroid, progenitors in bone marrow cells. RNA interference-mediated downregulation of BUBR1 also caused an increase in polyploidy formation in murine embryonic fibroblast cells and enhanced megakaryopoiesis in bone marrow progenitor cells. These and other results indicated that BUBR1 is essential for early embryonic development and normal hematopoiesis.
Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Baker et al. (2004) showed that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy (see 257300) along with a variety of progeroid features, including short life span, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat, and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wildtype mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.
Rao et al. (2005) found that mice haploinsufficient for both Bub1b and Apc (611731) developed 10 times more colonic tumors than mice deficient in Apc alone, and the tumors were of higher grades. Compound mutant mouse embryonic fibroblasts (MEFs) contained more beta-catenin (see 116806) and proliferated at a faster rate than wildtype or Bub1b +/- MEFs. Compound mutant MEFs also slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than wildtype, Bub1b +/-, or Apc +/- mice. Rao et al. (2005) concluded that BUB1B and APC functionally interact in regulating metaphase-anaphase transition, deregulation of which increases genomic instability and the development and progression of colorectal cancer.
Simmons et al. (2019) found that mice homozygous for a hypomorphic Bubr1 allele (Bubr1 H/H mice) had significantly reduced Bubr1 expression in various organs and embryonic fibroblasts and were markedly smaller than wildtype mice. However, reduced Bubr1 expression did not produce significant changes in embryonic brain development and did not induce microcephaly. In contrast, Bubr1 H/H mice with conditional knockout of Bubr1 in dorsal telencephalon (Bubr1 CKO mice) had more significant or nearly complete loss of Bubr1 expression, were even smaller than Bubr1 H/H mice, and had a severe cortical phenotype with microcephaly. Investigation of anatomic alterations during neurogenesis of Bubr1 CKO embryos showed that loss of Bubr1 reduced cortical ventricular surface and cortical progenitors, including apical and intermediate progenitors, which subsequently decreased neuronal production. The reduction of cortical progenitors was caused by massive cell death in progenitors and cortical neurons, leading to pathogenesis of microcephaly in Bubr1 CKO mice. Bubr1 was required for proper progression of mitosis, and consequently, loss of Bubr1 allowed NPCs to prematurely bypass the mitotic checkpoint, thereby accelerating progression of mitosis and decreasing the proportion of mitotic cells among cycling NPCs. More specifically, Bubr1 was crucial to maintain cells in metaphase, and loss of Bubr1 affected metaphase plate formation and shortened metaphase. The authors also reported absence of ependymal cells in the dorsal cortex of Bubr1 CKO mice, suggesting that Bubr1 may play a role in ependymal cell generation and/or maintenance.
Sieben et al. (2020) generated Bubr1 X753/L1002P mice mimicking the compound heterozygous BUBR1 mutations identified in biallelic MVA patients, in which X753 represented the BUBR1 frameshift mutation (2211insGTTA; 602860.0006) that yielded an unstable truncated protein, and L1002P corresponded to the L1012P (602860.0008) mutation. The Bubr1 L1002P allele yielded little protein due to elevated proteasomal degradation, and Bubr1 X753/L1002P mice died during early embryogenesis, likely due to severe mitotic defects. Due to embryonic lethality of Bubr1 X753/L1002P mice, the authors generated mice mimicking heterozygous carriers of 2 other MVA alleles, Bubr1 +/L1002P and Bubr1 +/-. Bubr1 +/L1002P and Bubr1 +/- mice displayed phenotypic heterogeneity, with different lifespans and different degrees of cancer susceptibility. Moreover, in contrast with the progeroid phenotype of Bubr1 +/X753 mice, Bubr1 +/- and Bubr1 +/L1002P mice showed little to no evidence of accelerated aging phenotypes. However, all 3 heterozygous carriers of Bubr1 MVA mutations displayed increased risk of tumor formation and increased aneuploidy in multiple tissues, key features of MVA syndrome. In line with the phenotypic heterogeneity, progeroid Bubr1 +/X753 mice also exhibited hyperactive mTorc1 (617034) signaling compared with the other models. The authors also generated Bubr1 H/X753 mice, but like Bubr1 -/H mice, Bubr1 H/X753 mice failed to thrive and died within 18 hours after birth. In contrast, Bubr1 H/L1002P mice had normal appearance at birth, were viable, had less severe growth retardation during postnatal development, and lived longer, compared with Bubr1 H/H mice. Like Bubr1 H/H mice, Bubr1 H/L1002P mice exhibited MVA features and recapitulated MVA syndrome in human. Moreover, Bubr1 H/L1002P, Bubr1 H/H, and Bubr1 H/X753 mice had a similar levels of Bubr1 protein reduction and displayed a similar mitotic phenotype characterized by severe mosaic aneuploidy. Despite these similarities, all 3 mutants showed MVA syndrome heterogeneity, especially progeroid heterogeneity. Further analysis indicated that these MVA mouse models displayed senescence-mediated pathologies and that the progeroid mechanisms in the models were mediated by accumulation of senescent cells, suggesting that diversity in senescent cell properties likely contributed to the progeroid heterogeneity among the different models.
In 1 of 19 colorectal cancer (see 114500) cell lines, Cahill et al. (1998) identified a germline C-to-T transition at codon 40 of BUB1B, resulting in a methionine-for-threonine substitution (T40M).
In 1 of 19 colorectal cancer (see 114500) cell lines, Cahill et al. (1998) identified a somatic deletion of a T at codon 1023 of BUB1B, leading to the removal of part of the kinase domain within the second conserved domain (CD2).
In a 14-year-old patient with mosaic variegated aneuploidy syndrome (MVA1; 257300) originally reported by Limwongse et al. (1999), Hanks et al. (2004) identified compound heterozygosity for 3 mutations in the BUB1B gene: a 580C-T transition, resulting in an arg194-to-ter (R194X) substitution, derived from the father, and 2 missense mutations derived from the mother, L844F (602860.0004) and Q921H (602860.0005). Without additional data it was difficult to determine which of these missense variants was pathogenic, but Hanks et al. (2004) noted that both mutations might affect BUB1B1 kinase activity and contribute to the phenotype. The L844F substitution arose from a 2530C-T transition, while the Q921H substitution arose from a 2763G-C transversion. The patient had intrauterine growth retardation, microcephaly, cryptorchidism, and embryonal rhabdomyosarcoma of the soft palate. Both parents had premature chromatid separation trait (PCS; 176430).
For discussion of the leu844-to-phe (L844F) mutation in the BUB1B gene that was found in compound heterozygous state in a patient with mosaic variegated aneuploidy syndrome (MVA1; 257300) by Hanks et al. (2004), see 602860.0003.
For discussion of the gln921-to-his (Q921H) mutation in the BUB1B gene that was found in compound heterozygous state in a patient with mosaic variegated aneuploidy syndrome (MVA1; 257300) by Hanks et al. (2004), see 602860.0003.
In affected members from 2 unrelated families with mosaic variegated aneuploidy syndrome (MVA1; 257300), Hanks et al. (2004) identified compound heterozygosity for 2 mutations in the BUB1B gene. Both families carried a 4-bp insertion (2211insGTTA), resulting in a frameshift after codon 738 with premature termination at codon 753. In one family, the other mutation was R814H (602860.0007) and in the other family, it was L1012P (602860.0008). The R814H substitution arose from a 2441G-A transition, while the L1012P substitution arose from a 3035T-C transition. In both families, the parents had premature chromatid separation trait (PCS; 176430).
For discussion of the arg814-to-his (R814H) mutation in the BUB1B gene that was found in compound heterozygous state in patients with mosaic variegated aneuploidy syndrome (MVA1; 257300) by Hanks et al. (2004), see 602860.0006.
For discussion of the leu1021-to-pro (L1012P) mutation in the BUB1B gene that was found in compound heterozygous state in patients with mosaic variegated aneuploidy syndrome (MVA1; 257300) by Hanks et al. (2004), see 602860.0006.
In 2 sibs with mosaic variegated aneuploidy syndrome (MVA1; 257300) originally reported by Plaja et al. (2001), Hanks et al. (2004) identified compound heterozygosity for 2 mutations in the BUB1B gene: a 1649G-A transition, resulting in an arg550-to-gln (R550Q) substitution, and a splice site acceptor mutation, IVS10-1G-T (602860.0010). RT-PCR analyses showed that IVS10-1G-T caused deletion of exon 11, which was predicted to result in a truncated protein of 482 amino acids. The first-born of the 2 sibs died at 1.5 years of age and showed intrauterine growth retardation, microcephaly, eye anomalies, thumb adduction, hemangioma, and embryonal rhabdomyosarcoma of the vagina. The other sib was the product of a pregnancy that ended in miscarriage 2 days after prenatal cytogenetic diagnosis of MVA. Both parents had premature chromatid separation trait (PCS; 176430).
For discussion of the splice site mutation in the BUB1B gene (IVS10-1G-T) that was found in compound heterozygous state in 2 sibs with mosaic variegated aneuploidy syndrome (MVA1; 257300) by Hanks et al. (2004), see 602860.0009.
In 2 affected individuals from 4 unrelated Japanese families with mosaic variegated aneuploidy syndrome (MVA1; 257300), Matsuura et al. (2006) identified a heterozygous 1-bp deletion (1833delT) in exon 15 of the BUB1B gene. The 1833delT mutation was also identified in the parents of 3 Japanese patients from 2 additional Japanese families in whom tissue from the affected children was not available. Haplotype analysis suggested a common founder in 3 of the 4 families. Three families also carried the BUB1B 6G3 haplotype, which was associated with decreased amounts of BUB1B transcript. In all 4 families, the parents had premature chromatid separation trait (PCS; 176430).
In a Japanese boy with mosaic variegated aneuploidy syndrome (MVA1; 257300), Matsuura et al. (2006) identified a heterozygous A-to-G transition in intron 10 of the BUB1B gene, resulting in a splice site mutation and premature termination of the protein. The unaffected father also had the mutation and had premature chromatid separation trait (PCS; 176430). The mother and the affected son both had the 6G3 haplotype, which was associated with decreased amounts of BUB1B transcripts. Western blot analysis of transformed lymphocytes from the 3 family members showed BUB1B band intensities to be 71% of normal controls in the mother, 57% in the father, and 22% in the affected son. Matsuura et al. (2006) concluded that the 6G3 haplotype resulted in a decreased amount of the BUB1B protein.
In a 68-year-old man, born of remotely consanguineous parents, with recurrent adult-onset gastrointestinal neoplasia associated with mosaic variegated aneuploidy (MVA1; 257300), Rio Frio et al. (2010) identified a homozygous A-to-G transition in intron 18 of the BUB1B gene, creating a de novo splice site that is favored over the authentic site. Although the mutant mRNA was found to be targeted by nonsense-mediated mRNA decay, a small amount (10 to 15%) of normal BUB1B was produced and correctly localized to the kinetochores of patient fibroblasts. However, the residual amount of protein was unable to maintain the spindle-assembly checkpoint, and thus the cells completed mitosis without cytokinesis, resulting in aneuploidy in some cells. Further studies of patient cells showed decreased BUB1B interaction with APC (611731). The patient developed adenocarcinoma of the ampulla of Vater at 34 years of age, followed by adenomatous polyps and multiple primary invasive adenocarcinomas of both the colon and the stomach about 2 decades later. Laboratory studies of patient lymphocytes and fibroblasts showed premature chromatid separation in 57 to 84% of cells and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities. The patient had no other features of the mosaic variegated aneuploidy syndrome, such as poor growth, microcephaly, or mental retardation. Heterozygous family members had low levels of premature chromatid separation (PCS; 176430) but were otherwise asymptomatic. The report expanded the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers.
Baker, D. J., Jeganathan, K. B., Cameron, J. D., Thompson, M., Juneja, S., Kopecka, A., Kumar, R., Jenkins, R. B., de Groen, P. C., Roche, P., van Deursen, J. M. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36: 744-749, 2004. [PubMed: 15208629] [Full Text: https://doi.org/10.1038/ng1382]
Bohers, E., Sarafan-Vasseur, N., Drouet, A., Paresy, M., Latouche, J.-B., Flaman, J.-M., Sesboue, R., Frebourg, T. Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy. Hum. Genet. 124: 473-478, 2008. [PubMed: 18932004] [Full Text: https://doi.org/10.1007/s00439-008-0572-y]
Cahill, D. P., Lengauer, C., Yu, J., Riggins, G. J., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300-303, 1998. [PubMed: 9521327] [Full Text: https://doi.org/10.1038/32688]
Davenport, J. W., Fernandes, E. R., Harris, L. D., Neale, G. A. M., Goorha, R. The mouse mitotic checkpoint gene Bub1b, a novel Bub1 family member, is expressed in a cell cycle-dependent manner. Genomics 55: 113-117, 1999. [PubMed: 9889005] [Full Text: https://doi.org/10.1006/geno.1998.5629]
Hanks, S., Coleman, K., Reid, S., Plaja, A., Firth, H., FitzPatrick, D., Kidd, A., Mehes, K., Nash, R., Robin, N., Shannon, N., Tolmie, J., Swansbury, J., Irrthum, A., Douglas, J., Rahman, N. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36: 1159-1161, 2004. [PubMed: 15475955] [Full Text: https://doi.org/10.1038/ng1449]
Homer, H., Gui, L., Carroll, J. A spindle assembly checkpoint protein functions in prophase I arrest and prometaphase progression. Science 326: 991-994, 2009. [PubMed: 19965510] [Full Text: https://doi.org/10.1126/science.1175326]
Lampson, M. A., Kapoor, T. M. The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nature Cell Biol. 7: 93-98, 2005. [PubMed: 15592459] [Full Text: https://doi.org/10.1038/ncb1208]
Limwongse, C., Schwartz, S., Bocian, M., Robin, N. H. Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma. Am. J. Med. Genet. 82: 20-24, 1999. [PubMed: 9916837] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990101)82:1<20::aid-ajmg4>3.0.co;2-5]
Mao, Y., Abrieu, A., Cleveland, D. W. Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell 114: 87-98, 2003. [PubMed: 12859900] [Full Text: https://doi.org/10.1016/s0092-8674(03)00475-6]
Matsuura, S., Matsumoto, Y., Morishima, K., Izumi, H., Matsumoto, H., Ito, E., Tsutsui, K., Kobayashi, J., Tauchi, H., Kajiwara, Y., Hama, S., Kurisu, K., Tahara, H., Oshimura, M., Komatsu, K., Ikeuchi, T., Kajii, T. Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am. J. Med. Genet. 140A: 358-367, 2006. [PubMed: 16411201] [Full Text: https://doi.org/10.1002/ajmg.a.31069]
Plaja, A., Vendrell, T., Smeets, D., Sarret, E., Gili, T., Catala, V., Mediano, C., Scheres, J. M. J. C. Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease. Am. J. Med. Genet. 98: 216-223, 2001. [PubMed: 11169558] [Full Text: https://doi.org/10.1002/1096-8628(20010122)98:3<216::aid-ajmg1091>3.0.co;2-0]
Rao, C. V., Yang, Y.-M., Swamy, M. V., Liu, T., Fang, Y., Mahmood, R., Jhanwar-Uniyal, M., Dai, W. Colonic tumorigenesis in BubR1 +/- Apc Min/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Nat. Acad. Sci. 102: 4365-4370, 2005. [PubMed: 15767571] [Full Text: https://doi.org/10.1073/pnas.0407822102]
Rio Frio, T., Lavoie, J., Hamel, N., Geyer, F. C., Kushner, Y. B., Novak, D. J., Wark, L., Capelli, C., Reis-Filho, J. S., Mai, S., Pastinen, T., Tischkowitz, M. D., Marcus, V. A., Foulkes, W. D. Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. New Eng. J. Med. 363: 2628-2637, 2010. [PubMed: 21190457] [Full Text: https://doi.org/10.1056/NEJMoa1006565]
Sieben, C. J., Jeganathan, K. B., Nelson, G. G., Sturmlechner, I., Zhang, C., van Deursen, W. H., Bakker, B., Foijer, F., Li, H., Baker, D. J., van Deursen, J. M. BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome. J. Clin. Invest. 130: 171-188, 2020. Note: Erratum: J. Clin. Invest. 130: 6188 only, 2020. [PubMed: 31738183] [Full Text: https://doi.org/10.1172/JCI126863]
Simmons, A. J., Park, R., Sterling, N. A., Jang, M.-H., van Deursen, J. M. A., Yen, T. J., Cho, S.-H., Kim, S. Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death. Hum. Molec. Genet. 28: 1822-1836, 2019. [PubMed: 30668728] [Full Text: https://doi.org/10.1093/hmg/ddz022]
Taylor, S. S., Ha, E., McKeon, F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J. Cell Biol. 142: 1-11, 1998. [PubMed: 9660858] [Full Text: https://doi.org/10.1083/jcb.142.1.1]
Wang, Q., Liu, T., Fang, Y., Xie, S., Huang, X., Mahmood, R., Ramaswamy, G., Sakamoto, K. M., Darzynkiewicz, Z., Xu, M., Dai, W. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 103: 1278-1285, 2004. [PubMed: 14576056] [Full Text: https://doi.org/10.1182/blood-2003-06-2158]