Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

WHSC1 (Wolf-Hirschhorn syndrome candidate 1)

Identity

Other namesMMSET
NSD2
REIIBP
TRX5
WHS
HGNC (Hugo) WHSC1
LocusID (NCBI) 7468
Location 4p16.3
Location_base_pair Starts at 1873123 and ends at 1983934 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order From the telomeric to centromeric end (Chesi et al., 1998).

DNA/RNA

Description Spans 120 Kb of genomic DNA and consists of 24 exons transcribed into a mRNA that undergoes alternative splicing (Marango et al., 2007).
Transcription Undergoes complex alternative splicing. Most primary trancripts splice directly to exon 3, which contains the proper translation initiation site, though small fraction of transcripts retain upstream sequence including exons 1 and 2 (Keats et al., 2005).

Protein

 
  Conserved domains present in MMSET variants (adapted from Keats et al., 2005).
Description Alternative splicing of exon 4 to 4a instead of 5 generates de MMSET III protein (273 amino acids, 32 kDa), due to the presence of an in-frame stop codon in exon 4a. Alternative splicing of exon 10 to 11 or 12 generates MMSET I (647 amino acids, 75 kDa) or the full-length MMSET II (1365 amino acids, 155 kDa) respectively, due to the presence of an in-frame stop codon in exon 11. A third transcript initiated within a middle intron of MMSET, encoding a mRNA comprising the 3'half of MMSET gene was identified and encodes a protein named RE-IIBP.
The long transcript, MMSET II, contains: 2 PWWP (proline-tryptophan-tryptophan-proline) domain, a HMG box (high mobility group), 4 PHD (plant-home domain)- type zinc finger motifs and a SET domain. MMSET I contains only a PWWP and a HMG domain and REIIBP, 2 PHD, a PWWP and a SET domain (Keats et al., 2005).
Expression Widely expressed.
It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients (Stec et al., 1998). Recently it has been shown that MMSET is highly expressed in different tumor types such as carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, bladder, female genitals and skin (Hudlebusch et al., 2011). It is also highly expressed and associated with aggressive neuroblastoma (Hudlebusch et al., 2011).
Localisation Homogenous pattern within the nucleus, excluded from the nucleolus.
Function Histone methyltransferase that leads to dimethylation of histone 3 lysine 36 (H3K36) (Marango et al., 2008; Martinez-Garcia et al., 2011; Kuo et al., 2011). WHSC1 is involved in the cellular response to DNA damage through its activity on H4K20 residue (Hajdu et al., 2011; Pei et al., 2011).

Implicated in

Entity Multiple myeloma (MM)
Note WHSC1 was identified as a gene involved in the t(4;14)(p16;q32) translocation present in approximately 15% to 20% of MM (Chesi et al., 1998). This subtype of myeloma with t(4;14)(p16;q32) has a poor prognosis with frequent relapse after autologous stem-cell transplantation (Moreau et al., 2002; Chang et al., 2004).
 
The t(4;14) Translocation Identifies MMSET as an oncogene in Multiple Myeloma. The gene rearrangement links the Eµ enhancer 5' to MMSET, driving transcription of MMSET from the telomeric-centromeric direction. The reciprocal translocation links an Ig enhancer 3' to the FGFR3 locus stimulating transcription in the centromeric-telomeric direction.
  
Entity Glioblastoma
Note WHSC1 expression level is correlated with glioma grade, and it appears to be directly involved in the proliferative capacity of GBM cells in vitro (Li et al., 2008).
  
Entity Neuroblastoma
Note MMSET is highly expressed in 75% neuroblastomas and is associated with aggressiveness. MMSET is associated with poor prognostic markers, poor survival, and progression; and is required for proliferation of neuroblastoma cells (Hudlebusch et al., 2011).
  
Entity Urinary bladder cancer
Note In urinary bladder cancer, MMSET protein was detected in 40% of the cases and was associated with aggressiveness: expression levels correlated with poor prognostic markers (stage, grade, age, and type of tumor growth), and progression (Hudlebusch et al., 2011).
  
Entity Prostate cancer
Note Analysis of microarray databases indicates that MMSET expression rises in the progression from benign prostatic epithelium to localized and metastatic PCa. Overexpression of MMSET in RWPE-1 cells is accompanied by an epithelial to mesenchymal transition (EMT), characterized by a change in cell morphology and increased expression of mesenchymal markers vimentin and N-cadherin. Twist1, an EMT promoting gene, was strongly regulated by MMSET (Ezponda-Itoiz et al., 2012).
  
Entity Wolf-Hirschhorn syndrome (WHS)
Note Wolf-Hirshhorn syndrome is caused by a partial deletion of chromosome 4p, particularly in the region of WHSC1 and WHSC2. About 87% of cases represent a de novo deletion, while about 13% are inherited from a parent with a chromosome translocation.
  

External links

Nomenclature
HGNC (Hugo)WHSC1   12766
Cards
AtlasWHSC1ID42809ch4p16
Entrez_Gene (NCBI)WHSC1  7468  Wolf-Hirschhorn syndrome candidate 1
GeneCards (Weizmann)WHSC1
Ensembl (Hinxton)ENSG00000109685 [Gene_View]  chr4:1873123-1983934 [Contig_View]  WHSC1 [Vega]
ICGC DataPortalENSG00000109685
cBioPortalWHSC1
AceView (NCBI)WHSC1
Genatlas (Paris)WHSC1
WikiGenes7468
SOURCE (Princeton)NM_001042424 NM_007331 NM_014919 NM_133330 NM_133331 NM_133332 NM_133333 NM_133334 NM_133335 NM_133336
Genomic and cartography
GoldenPath (UCSC)WHSC1  -  4p16.3   chr4:1873123-1983934 +  4p16.3   [Description]    (hg19-Feb_2009)
EnsemblWHSC1 - 4p16.3 [CytoView]
Mapping of homologs : NCBIWHSC1 [Mapview]
OMIM194190   602952   
Gene and transcription
Genbank (Entrez)AB029013 AF071593 AF071594 AF083386 AF083387
RefSeq transcript (Entrez)NM_001042424 NM_007331 NM_014919 NM_133330 NM_133331 NM_133332 NM_133333 NM_133334 NM_133335 NM_133336
RefSeq genomic (Entrez)AC_000136 NC_000004 NC_018915 NG_009269 NT_006051 NW_001838896 NW_004929314
Consensus coding sequences : CCDS (NCBI)WHSC1
Cluster EST : UnigeneHs.113876 [ NCBI ]
CGAP (NCI)Hs.113876
Alternative Splicing : Fast-db (Paris)GSHG0022407
Alternative Splicing GalleryENSG00000109685
Gene ExpressionWHSC1 [ NCBI-GEO ]     WHSC1 [ SEEK ]   WHSC1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO96028 (Uniprot)
NextProtO96028  [Medical]
With graphics : InterProO96028
Splice isoforms : SwissVarO96028 (Swissvar)
Catalytic activity : Enzyme2.1.1.43 [ Enzyme-Expasy ]   2.1.1.432.1.1.43 [ IntEnz-EBI ]   2.1.1.43 [ BRENDA ]   2.1.1.43 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)AWS (PS51215)    HMG_BOX_2 (PS50118)    POST_SET (PS50868)    PWWP (PS50812)    SET (PS50280)    ZF_PHD_1 (PS01359)    ZF_PHD_2 (PS50016)   
Domains : Interpro (EBI)AWS [organisation]   HMG_box_dom [organisation]   Post-SET_dom [organisation]   PWWP_dom [organisation]   SET_dom [organisation]   Zinc_finger_PHD-type_CS [organisation]   Znf_FYVE_PHD [organisation]   Znf_PHD [organisation]   Znf_PHD-finger [organisation]   Znf_RING [organisation]   Znf_RING/FYVE/PHD [organisation]  
Related proteins : CluSTrO96028
Domain families : Pfam (Sanger)HMG_box (PF00505)    PHD (PF00628)    PWWP (PF00855)    SET (PF00856)   
Domain families : Pfam (NCBI)pfam00505    pfam00628    pfam00855    pfam00856   
Domain families : Smart (EMBL)AWS (SM00570)  HMG (SM00398)  PHD (SM00249)  PostSET (SM00508)  PWWP (SM00293)  RING (SM00184)  SET (SM00317)  
DMDM Disease mutations7468
Blocks (Seattle)O96028
Human Protein AtlasENSG00000109685 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO96028
HPRD04259
IPIIPI00218240   IPI00792674   IPI00107486   IPI00334604   IPI00790144   IPI00470433   IPI00902751   IPI00107487   IPI00966823   IPI00967969   IPI00969210   IPI00966493   IPI00966240   
Protein Interaction databases
DIP (DOE-UCLA)O96028
IntAct (EBI)O96028
FunCoupENSG00000109685
BioGRIDWHSC1
InParanoidO96028
Interologous Interaction database O96028
IntegromeDBWHSC1
STRING (EMBL)WHSC1
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  membranous septum morphogenesis  atrial septum primum morphogenesis  atrial septum secundum morphogenesis  DNA binding  chromatin binding  protein binding  nucleus  chromosome  nucleolus  cytoplasm  transcription, DNA-templated  zinc ion binding  anatomical structure morphogenesis  histone-lysine N-methyltransferase activity  nuclear membrane  bone development  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  membranous septum morphogenesis  atrial septum primum morphogenesis  atrial septum secundum morphogenesis  DNA binding  chromatin binding  protein binding  nucleus  chromosome  nucleolus  cytoplasm  transcription, DNA-templated  zinc ion binding  anatomical structure morphogenesis  histone-lysine N-methyltransferase activity  nuclear membrane  bone development  
Pathways : KEGGLysine degradation    Transcriptional misregulation in cancer   
Protein Interaction DatabaseWHSC1
Wikipedia pathwaysWHSC1
Gene fusion - rearrangments
Rearrangement : TICdb- [-]  -  WHSC1 [11q23.3]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)WHSC1
snp3D : Map Gene to Disease7468
SNP (GeneSNP Utah)WHSC1
SNP : HGBaseWHSC1
Genetic variants : HAPMAPWHSC1
Exome VariantWHSC1
1000_GenomesWHSC1 
ICGC programENSG00000109685 
Cancer Gene: CensusWHSC1 
Somatic Mutations in Cancer : COSMICWHSC1 
CONAN: Copy Number AnalysisWHSC1 
Mutations and Diseases : HGMDWHSC1
Genomic VariantsWHSC1  WHSC1 [DGVbeta]
dbVarWHSC1
ClinVarWHSC1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM194190    602952   
MedgenWHSC1
GENETestsWHSC1
Disease Genetic AssociationWHSC1
Huge Navigator WHSC1 [HugePedia]  WHSC1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneWHSC1
Homology/Alignments : Family Browser (UCSC)WHSC1
Phylogenetic Trees/Animal Genes : TreeFamWHSC1
Chemical/Protein Interactions : CTD7468
Chemical/Pharm GKB GenePA37369
Clinical trialWHSC1
Cancer Resource (Charite)ENSG00000109685
Other databases
Probes
Litterature
PubMed56 Pubmed reference(s) in Entrez
CoreMineWHSC1
iHOPWHSC1

Bibliography

The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.
Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL.
Blood. 1998 Nov 1;92(9):3025-34.
PMID 9787135
 
WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.
Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, Altherr MR, den Dunnen JT.
Hum Mol Genet. 1998 Jul;7(7):1071-82.
PMID 9618163
 
Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy.
Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, Bataille R, Avet-Loiseau H; Intergroupe Francophone du Myelome.
Blood. 2002 Sep 1;100(5):1579-83.
PMID 12176874
 
The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant.
Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D, Chun K, Keith Stewart A.
Br J Haematol. 2004 Apr;125(1):64-8.
PMID 15015970
 
Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.
Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR, Pilarski LM.
Blood. 2005 May 15;105(10):4060-9. Epub 2005 Jan 27.
PMID 15677557
 
Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas.
Li J, Yin C, Okamoto H, Mushlin H, Balgley BM, Lee CS, Yuan K, Ikejiri B, Glasker S, Vortmeyer AO, Oldfield EH, Weil RJ, Zhuang Z.
Neuro Oncol. 2008 Feb;10(1):45-51. Epub 2008 Jan 8.
PMID 18182627
 
The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.
Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A, Martinez-Martinez Y, Chesi M, Bergsagel PL, Zhou MM, Waxman S, Leibovitch BA, Walsh MJ, Licht JD.
Blood. 2008 Mar 15;111(6):3145-54. Epub 2007 Dec 21.
PMID 18156491
 
Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage.
Hajdu I, Ciccia A, Lewis SM, Elledge SJ.
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13130-4. Epub 2011 Jul 25.
PMID 21788515
 
The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors.
Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV, Jorgensen M, Sauter G, Helin K.
Clin Cancer Res. 2011 May 1;17(9):2919-33. Epub 2011 Mar 8.
PMID 21385930
 
MMSET is highly expressed and associated with aggressiveness in neuroblastoma.
Hudlebusch HR, Skotte J, Santoni-Rugiu E, Zimling ZG, Lees MJ, Simon R, Sauter G, Rota R, De Ioris MA, Quarto M, Johansen JV, Jorgensen M, Rechnitzer C, Maroun LL, Schroder H, Petersen BL, Helin K.
Cancer Res. 2011 Jun 15;71(12):4226-35. Epub 2011 Apr 28.
PMID 21527557
 
NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.
Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, Li W, Gozani O.
Mol Cell. 2011 Nov 18;44(4):609-20.
PMID 22099308
 
The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells.
Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L, Heffner A, Will C, Lamy L, Staudt LM, Levens DL, Kelleher NL, Licht JD.
Blood. 2011 Jan 6;117(1):211-20. Epub 2010 Oct 25.
PMID 20974671
 
MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.
Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F, Bergsagel PL, Wang L, You Z, Lou Z.
Nature. 2011 Feb 3;470(7332):124-8.
PMID 21293379
 
The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.
Ezponda T, Popovic R, Shah MY, Martinez-Garcia E, Zheng Y, Min DJ, Will C, Neri A, Kelleher NL, Yu J, Licht JD.
Oncogene. 2012 Jul 16. doi: 10.1038/onc.2012.297. [Epub ahead of print]
PMID 22797064
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written11-2008Eva Martinez-Garcia, Jonathan D Licht
Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA
Updated05-2012Eva Martinez-Garcia, Jonathan D Licht
Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA

Citation

This paper should be referenced as such :
Martinez-Garcia, E ; Licht, JD
WHSC1 (Wolf-Hirschhorn syndrome candidate 1)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):743-745.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Martinez-Garcia, E ; Licht, JD. WHSC1 (Wolf-Hirschhorn syndrome candidate 1). Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):743-745.
http://documents.irevues.inist.fr/bitstream/handle/2042/48152/1/05-2012-WHSC1ID42809ch4p16.pdf
URL : http://AtlasGeneticsOncology.org/Genes/WHSC1ID42809ch4p16.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Jul 11 17:02:21 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.