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

Identity

Other namesBub1A
BUBR1
MAD3L
SSK1
HGNC (Hugo) BUB1B
LocusID (NCBI) 701
Location 15q15.1
Location_base_pair Starts at 40453210 and ends at 40513337 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Figure 1. Schematic representation of BUB1B demonstrating the relative exon sizes.
Description BUB1B spans 60 kb and is composed of 23 exons.

Protein

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 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.
  

To be noted

Biallelic mutations in CEP57 have also been identified in individuals with MVA syndrome.

External links

Nomenclature
HGNC (Hugo)BUB1B   1149
Cards
AtlasBUB1BID854ch15q15
Entrez_Gene (NCBI)BUB1B  701  BUB1 mitotic checkpoint serine/threonine kinase B
GeneCards (Weizmann)BUB1B
Ensembl (Hinxton)ENSG00000156970 [Gene_View]  chr15:40453210-40513337 [Contig_View]  BUB1B [Vega]
ICGC DataPortalENSG00000156970
cBioPortalBUB1B
AceView (NCBI)BUB1B
Genatlas (Paris)BUB1B
WikiGenes701
SOURCE (Princeton)NM_001211
Genomic and cartography
GoldenPath (UCSC)BUB1B  -  15q15.1   chr15:40453210-40513337 +  15q15   [Description]    (hg19-Feb_2009)
EnsemblBUB1B - 15q15 [CytoView]
Mapping of homologs : NCBIBUB1B [Mapview]
OMIM176430   257300   602860   
Gene and transcription
Genbank (Entrez)AB208782 AF035933 AF046079 AF046918 AF053306
RefSeq transcript (Entrez)NM_001211
RefSeq genomic (Entrez)AC_000147 NC_000015 NC_018926 NG_016338 NT_010194 NW_001838214 NW_004929398
Consensus coding sequences : CCDS (NCBI)BUB1B
Cluster EST : UnigeneHs.513645 [ NCBI ]
CGAP (NCI)Hs.513645
Alternative Splicing : Fast-db (Paris)GSHG0009768
Alternative Splicing GalleryENSG00000156970
Gene ExpressionBUB1B [ NCBI-GEO ]     BUB1B [ SEEK ]   BUB1B [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO60566 (Uniprot)
NextProtO60566  [Medical]
With graphics : InterProO60566
Splice isoforms : SwissVarO60566 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)BUB1_N (PS51489)   
Domains : Interpro (EBI)Bub1/Mad3 [organisation]   Kinase-like_dom [organisation]   Mad3_BUB1_I [organisation]   Prot_kinase_dom [organisation]  
Related proteins : CluSTrO60566
Domain families : Pfam (Sanger)Mad3_BUB1_I (PF08311)    Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam08311    pfam00069   
Domain families : Smart (EMBL)Mad3_BUB1_I (SM00777)  
DMDM Disease mutations701
Blocks (Seattle)O60566
PDB (SRS)2WVI    3SI5    4GGD   
PDB (PDBSum)2WVI    3SI5    4GGD   
PDB (IMB)2WVI    3SI5    4GGD   
PDB (RSDB)2WVI    3SI5    4GGD   
Human Protein AtlasENSG00000156970 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO60566
HPRD04176
IPIIPI00141933   IPI00922915   IPI00921844   IPI00952610   
Protein Interaction databases
DIP (DOE-UCLA)O60566
IntAct (EBI)O60566
FunCoupENSG00000156970
BioGRIDBUB1B
InParanoidO60566
Interologous Interaction database O60566
IntegromeDBBUB1B
STRING (EMBL)BUB1B
Ontologies - Pathways
Ontology : AmiGOmitotic cell cycle  kinetochore  kinetochore  kinetochore  kinetochore  condensed chromosome kinetochore  condensed nuclear chromosome kinetochore  condensed chromosome outer kinetochore  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  anaphase-promoting complex  cytoplasm  microtubule organizing center  cytosol  protein phosphorylation  apoptotic process  cell cycle  spindle organization  mitotic nuclear division  metaphase/anaphase transition of mitotic cell cycle  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  cell proliferation  anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process  protein localization to kinetochore  phosphatidylinositol-mediated signaling  perinuclear region of cytoplasm  spindle midzone  negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  protein localization to chromosome, centromeric region  
Ontology : EGO-EBImitotic cell cycle  kinetochore  kinetochore  kinetochore  kinetochore  condensed chromosome kinetochore  condensed nuclear chromosome kinetochore  condensed chromosome outer kinetochore  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  anaphase-promoting complex  cytoplasm  microtubule organizing center  cytosol  protein phosphorylation  apoptotic process  cell cycle  spindle organization  mitotic nuclear division  metaphase/anaphase transition of mitotic cell cycle  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  cell proliferation  anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process  protein localization to kinetochore  phosphatidylinositol-mediated signaling  perinuclear region of cytoplasm  spindle midzone  negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  protein localization to chromosome, centromeric region  
Pathways : KEGGCell cycle    HTLV-I infection   
Protein Interaction DatabaseBUB1B
Wikipedia pathwaysBUB1B
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)BUB1B
snp3D : Map Gene to Disease701
SNP (GeneSNP Utah)BUB1B
SNP : HGBaseBUB1B
Genetic variants : HAPMAPBUB1B
Exome VariantBUB1B
1000_GenomesBUB1B 
ICGC programENSG00000156970 
Cancer Gene: CensusBUB1B 
Somatic Mutations in Cancer : COSMICBUB1B 
CONAN: Copy Number AnalysisBUB1B 
Mutations and Diseases : HGMDBUB1B
Mutations and Diseases : intOGenBUB1B
Genomic VariantsBUB1B  BUB1B [DGVbeta]
dbVarBUB1B
ClinVarBUB1B
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM176430    257300    602860   
MedgenBUB1B
GENETestsBUB1B
Disease Genetic AssociationBUB1B
Huge Navigator BUB1B [HugePedia]  BUB1B [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneBUB1B
Homology/Alignments : Family Browser (UCSC)BUB1B
Phylogenetic Trees/Animal Genes : TreeFamBUB1B
Chemical/Protein Interactions : CTD701
Chemical/Pharm GKB GenePA82
Clinical trialBUB1B
Cancer Resource (Charite)ENSG00000156970
Other databases
Probes
Litterature
PubMed148 Pubmed reference(s) in Entrez
CoreMineBUB1B
iHOPBUB1B
OncoSearchBUB1B

Bibliography

Mutations of mitotic checkpoint genes in human cancers.
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B.
Nature. 1998 Mar 19;392(6673):300-3.
PMID 9521327
 
The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase.
Taylor SS, Ha E, McKeon F.
J Cell Biol. 1998 Jul 13;142(1):1-11.
PMID 9660858
 
Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.
Limwongse C, Schwartz S, Bocian M, Robin NH.
Am J Med Genet. 1999 Jan 1;82(1):20-4. (REVIEW)
PMID 9916837
 
Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease.
Plaja A, Vendrell T, Smeets D, Sarret E, Gili T, Catala V, Mediano C, Scheres JM.
Am J Med Genet. 2001 Jan 22;98(3):216-23. (REVIEW)
PMID 11169558
 
Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects.
Lane AH, Aijaz N, Galvin-Parton P, Lanman J, Mangano R, Wilson TA.
Am J Med Genet. 2002 Jul 1;110(3):273-7.
PMID 12116237
 
The spindle checkpoint, aneuploidy, and cancer.
Bharadwaj R, Yu H.
Oncogene. 2004 Mar 15;23(11):2016-27. (REVIEW)
PMID 15021889
 
Prenatal diagnosis of premature centromere division-related mosaic variegated aneuploidy.
Chen CP, Lee CC, Chen WL, Wang W, Tzen CY.
Prenat Diagn. 2004 Jan;24(1):19-25. (REVIEW)
PMID 14755404
 
Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.
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.
Nat Genet. 2004 Nov;36(11):1159-61. Epub 2004 Oct 10.
PMID 15475955
 
The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.
Lampson MA, Kapoor TM.
Nat Cell Biol. 2005 Jan;7(1):93-8. Epub 2004 Dec 12.
PMID 15592459
 
Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.
Hanks S, Coleman K, Summersgill B, Messahel B, Williamson D, Pritchard-Jones K, Strefford J, Swansbury J, Plaja A, Shipley J, Rahman N.
Cancer Lett. 2006 Aug 8;239(2):234-8. Epub 2005 Sep 22.
PMID 16182441
 
Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.
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.
Am J Med Genet A. 2006 Feb 15;140(4):358-67.
PMID 16411201
 
The spindle-assembly checkpoint in space and time.
Musacchio A, Salmon ED.
Nat Rev Mol Cell Biol. 2007 May;8(5):379-93. Epub 2007 Apr 11. (REVIEW)
PMID 17426725
 
Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes.
Garcia-Castillo H, Vasquez-Velasquez AI, Rivera H, Barros-Nunez P.
Am J Med Genet A. 2008 Jul 1;146A(13):1687-95. (REVIEW)
PMID 18548531
 
BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells.
Izumi H, Matsumoto Y, Ikeuchi T, Saya H, Kajii T, Matsuura S.
Oncogene. 2009 Aug 6;28(31):2806-20. Epub 2009 Jun 8.
PMID 19503101
 
Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy.
Suijkerbuijk SJ, van Osch MH, Bos FL, Hanks S, Rahman N, Kops GJ.
Cancer Res. 2010 Jun 15;70(12):4891-900. Epub 2010 Jun 1.
PMID 20516114
 
Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.
Snape K, Hanks S, Ruark E, Barros-Nunez P, Elliott A, Murray A, Lane AH, Shannon N, Callier P, Chitayat D, Clayton-Smith J, Fitzpatrick DR, Gisselsson D, Jacquemont S, Asakura-Hay K, Micale MA, Tolmie J, Turnpenny PD, Wright M, Douglas J, Rahman N.
Nat Genet. 2011 Jun;43(6):527-9. Epub 2011 May 8.
PMID 21552266
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2005Sandra Hanks, Nazneen Rahman
Medical Genetics Section of Cancer Genetics, Brookes Lawley Building Institute of Cancer Research, 15 Cotswold Road, Sutton Surrey, SM2 5NG, UK
Updated03-2012Sandra Hanks, Katie Snape, Nazneen Rahman
Institute of Cancer Research, Division of Genetics and Epidemiology, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK

Citation

This paper should be referenced as such :
Hanks, S ; Snape, K ; Rahman, N
BUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):518-520.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Hanks, S ; Snape, K ; Rahman, N. BUB1B (budding uninhibited by benzimidazoles 1 homolog beta (yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):518-520.
http://documents.irevues.inist.fr/bitstream/handle/2042/47482/03-2012-BUB1BID854ch15q15.pdf
URL : http://AtlasGeneticsOncology.org/Genes/BUB1BID854ch15q15.html

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