BUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast))

2012-03-01 Sandra Hanks , Katie Snape , Nazneen Rahman Affiliation

Medical Genetics Section of Cancer Genetics, Brookes Lawley Building Institute of Cancer Research, 15 Cotswold Road, Sutton Surrey, SM2 5NG, UK

Identity

HGNC

BUB1B

LOCATION

15q15.1

LOCUSID

701

ALIAS

BUB1beta,BUBR1,Bub1A,MAD3L,MVA1,SSK1,hBUBR1

FUSION GENES

Show Gene Fusions

DNA/RNA

Figure 1. Schematic representation of BUB1B demonstrating the relative exon sizes.

Description

BUB1B spans 60 kb and is composed of 23 exons.

Proteins

Note

Protein name: BUBR1.

Figure 2. Schematic representation of BUBR1 demonstrating significant functional or structural domains.

Description

1050 amino acids, 120 kDa.

Expression

Ubiquituously expressed. Preferentially expressed in tissues with a high mitotic index.

Localisation

Cytoplasmic in interphase cells. Bound to BUB3 or CENPE, it can be localised to nuclear kinetochores. BUBR1 also localises to centrosomes during interphase.

Function

A central component of the mitotic spindle checkpoint that directly inhibits the anaphase-promoting complex/cyclosome until sister chromatids are correctly attached to the spindle, thus ensuring proper chromosome segregation during cell division. Also binds the motor protein CENPE, an interaction required for regulation of kinetochore-microtubule interactions and checkpoint signalling.

Homology

BUBR1 is the mammalian homologue of yeast Mad3, a significant difference being that BUBR1 possesses a kinase domain which is absent in Mad3.

Mutations

Note

Cells from BUB1B mutation-positive cases demonstrate an abnormal response to nocodazole-induced mitotic checkpoint activation.

Figure 3. Schematic representation of BUB1B demonstrating the relative exon sizes and positions of known mutations. Truncating mutations are depicted above the figure, with missense mutations below. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours. Monoallelic mutations are represented by black lines and font.

Germinal

Biallelic germline mutations have been found in eight MVA pedigrees (figure 3). Each family carries one missense mutation and one mutation that results in premature protein truncation or an absent transcript. Monoallelic truncating mutations have also been reported in several cases.

Implicated in

Entity name

Mosaic variegated aneuploidy (MVA)

Note

MVA is a rare recessive condition characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay and a broad spectrum of additional congenital abnormalities and medical conditions may also occur.

Prognosis

There is early mortality in a significant proportion of cases due to failure to thrive and/or complications of congenital abnormalities, epilepsy, infections or malignancy.

Cytogenetics

The proportion of aneuploid cells varies but is usually >10% and is substantially greater than in normal individuals.

Oncogenesis

The risk of malignancy in MVA is high, with Wilms tumour, rhabdomyosarcoma, leukaemia and granulosa cell tumour of the ovary reported in several cases. Myelodysplastic syndrome has also been observed. Three of the eight cases with biallelic BUB1B mutations developed a rhabdomyosarcoma and one individual developed a granulosa cell tumour of the ovary. Wilms tumour and rhabdomyosarcoma have been reported in monoallelic BUB1B cases.

Bibliography

Pubmed ID	Last Year	Title	Authors
15021889	2004	The spindle checkpoint, aneuploidy, and cancer.	Bharadwaj R et al
9521327	1998	Mutations of mitotic checkpoint genes in human cancers.	Cahill DP et al
14755404	2004	Prenatal diagnosis of premature centromere division-related mosaic variegated aneuploidy.	Chen CP et al
18548531	2008	Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.	García-Castillo H et al
16182441	2006	Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.	Hanks S et al
19503101	2009	BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells.	Izumi H et al
15592459	2005	The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.	Lampson MA et al
12116237	2002	Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects.	Lane AH et al
9916837	1999	Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.	Limwongse C et al
16411201	2006	Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.	Matsuura S et al
17426725	2007	The spindle-assembly checkpoint in space and time.	Musacchio A et al
11169558	2001	Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease.	Plaja A et al
21552266	2011	Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.	Snape K et al
20516114	2010	Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.	Suijkerbuijk SJ et al
9660858	1998	The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase.	Taylor SS et al

Other Information

Locus ID:

NCBI: 701
MIM: 602860
HGNC: 1149
Ensembl: ENSG00000156970

Variants:

dbSNP: 701
ClinVar: 701
TCGA: ENSG00000156970
COSMIC: BUB1B

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000156970	ENST00000287598	O60566
ENSG00000156970	ENST00000412359	O60566
ENSG00000156970	ENST00000558715	H0YN44
ENSG00000156970	ENST00000559733	H0YMK5

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cell cycle	KEGG	ko04110
Cell cycle	KEGG	hsa04110
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Rho GTPases	REACTOME	R-HSA-194315
RHO GTPase Effectors	REACTOME	R-HSA-195258
RHO GTPases Activate Formins	REACTOME	R-HSA-5663220
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle Checkpoints	REACTOME	R-HSA-69620
Mitotic Spindle Checkpoint	REACTOME	R-HSA-69618
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	REACTOME	R-HSA-141405
Inactivation of APC/C via direct inhibition of the APC/C complex	REACTOME	R-HSA-141430
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
M Phase	REACTOME	R-HSA-68886
Mitotic Prometaphase	REACTOME	R-HSA-68877
Resolution of Sister Chromatid Cohesion	REACTOME	R-HSA-2500257
Mitotic Metaphase and Anaphase	REACTOME	R-HSA-2555396
Mitotic Anaphase	REACTOME	R-HSA-68882
Separation of Sister Chromatids	REACTOME	R-HSA-2467813
Regulation of mitotic cell cycle	REACTOME	R-HSA-453276
APC/C-mediated degradation of cell cycle proteins	REACTOME	R-HSA-174143
Regulation of APC/C activators between G1/S and early anaphase	REACTOME	R-HSA-176408
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	REACTOME	R-HSA-176814
APC/C:Cdc20 mediated degradation of mitotic proteins	REACTOME	R-HSA-176409
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	REACTOME	R-HSA-179419
Cdc20:Phospho-APC/C mediated degradation of Cyclin A	REACTOME	R-HSA-174184
APC-Cdc20 mediated degradation of Nek2A	REACTOME	R-HSA-179409

References

Pubmed ID	Year	Title	Citations
15475955	2004	Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.	178
19154722	2009	Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding.	128
15592459	2005	The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.	127
11907259	2002	Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex.	122
23079597	2012	Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments.	100
11792804	2001	Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells.	88
19139432	2009	Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival.	82
23345399	2013	Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression.	73
22100920	2011	p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit.	70
16144904	2005	Microtubule capture by CENP-E silences BubR1-dependent mitotic checkpoint signaling.	62

Citation

Sandra Hanks ; Katie Snape ; Nazneen Rahman

BUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast))

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version: http://atlasgeneticsoncology.org/gene/854/bub1b

Historical Card

2005-07-01 BUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast)) by Sandra Hanks,Nazneen Rahman Affiliation

Medical Genetics Section of Cancer Genetics, Brookes Lawley Building Institute of Cancer Research, 15 Cotswold Road, Sutton Surrey, SM2 5NG, UK