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FUS (fusion involved in t (12;16) in malignant liposarcoma)

Identity

Other namesTLS (translocated in liposarcoma)
HGNC (Hugo) FUS
LocusID (NCBI) 2521
Location 16p11.2
Location_base_pair Starts at 31191431 and ends at 31206192 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The gene has 15 exons, and the total genomic sequence spanning the FUS gene is approx. 12 Kb.
Transcription Transcript lenght: 1,9 Kb. There are two isoforms produced by an alternative splicing that involved the exon 4a (145 bp) or the exon 4b (142 bp).

Protein

 
Description 526 amino acids (isoform with the exon 4a) or 525 aa (isoform with the exon 4b), 68 Kda. The protein contains different domains:
  • a N-terminal SYQG-rich region;
  • a RGG-rich region;
  • a RNA binding domain;
  • a RGG-rich region;
  • a Cys2/Cys2-zinc finger motif and;
  • a C-terminal RGG-rich region.

    • Expression FUS is expressed in a housekeeping pattern.
    Localisation Nuclear, although FUS shuttles from the nucleus to the cytoplasm in a large complex that contains mRNA and hnRNPs.
    Function FUS is a RNA-binding protein that is identical to hnRNP P2 and may be implicated in mRNA metabolism. FUS seems to have a function as a heterogeneous ribonuclear protein (hnRNP)-like chaperone of RNA. In addition, it has been suggested that FUS might have a role in the BCR/ABL-mediated leukemogenesis.
    Homology FUS forms a sub-family of RNA binding proteins with EWS and RBP56/hTAFII68. FUS has homologous in mouse (fus), rat (pigpen) and Drosophila (Cabeza/SARFH).

    Mutations

    Germinal In the mouse, germline mutation in the fus gene produces male sterility, sensitivity to radiation, defective B-lymphocyte development and activation, chromosomal instability and perinatal death.

    Implicated in

    Note The FUS gene is implicated in several chromosomal translocations associated to both solid tumors and leukemias. The result of these chromosomal translocations are gene fusions. FUS contributes to these fusions with its N-terminal part, just before the RNA-binding domain. This domain confers to the fusion protein a transcriptional activation domain. These fusion genes generated as a result of chromosomal rearragements are used to monitor diagnosis and treatment.
     
      
    Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/ATF-1.
    Disease Angiomatoid fibrous histiocytoma (AFH).
    Hybrid/Mutated Gene FUS was interrupted at codon 175 (exon 5) and fused to codon 110 (exon 5) of ATF-1, resulting in an in-frame junction with a glycine to valine (GGT to GTT) transition.
      
    Entity t(7;16)(q33;p11) chromosomal translocation. It produces the fusion protein FUS/CREB3L2 (also known as BBF2H7).
    Disease Low grade fibromyxoid sarcoma (LGFMS).
    Hybrid/Mutated Gene The breakpoints in the fusion transcripts are produced between the exons 6 or 7 of FUS and the exon 5 of CREB3L2.
      
    Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3 (also known as CHOP).
    Disease Myxoid liposarcoma (MLS).
    Hybrid/Mutated Gene 9 different types of fusions between the genes FUS and DDIT3 have been reported. The most frequent rearragements join the exons 5, 7 or 8 of FUS with the exon 2 of DDIT3.
    Oncogenesis The unequivocally relation between FUS/DDIT3 and the MLS was shown by the generation of a transgenic mouse model expressing FUS/DDIT3 from a housekeeping promoter.
      
    Entity t(16;21)(p11;q22) chromosomal translocation. It produces the fusion protein FUS/ERG.
    Disease Acute myeloid leukemia (AML).
    Hybrid/Mutated Gene The junction of both genes is produced between the exons 6 or 7 of FUS and the exon 9 of ERG,or between the exon 8 of FUS and the exon 7 of ERG.
      

    Breakpoints

     

    External links

    Nomenclature
    HGNC (Hugo)FUS   4010
    Cards
    AtlasFUSID44
    Entrez_Gene (NCBI)FUS  2521  fused in sarcoma
    GeneCards (Weizmann)FUS
    Ensembl (Hinxton)ENSG00000089280 [Gene_View]  chr16:31191431-31206192 [Contig_View]  FUS [Vega]
    AceView (NCBI)FUS
    Genatlas (Paris)FUS
    WikiGenes2521
    SOURCE (Princeton)NM_001010850 NM_001170634 NM_001170937 NM_004960
    Genomic and cartography
    GoldenPath (UCSC)FUS  -  16p11.2   chr16:31191431-31206192 +  16p11.2   [Description]    (hg19-Feb_2009)
    EnsemblFUS - 16p11.2 [CytoView]
    Mapping of homologs : NCBIFUS [Mapview]
    OMIM137070   608030   614782   
    Gene and transcription
    Genbank (Entrez)AB208902 AI333366 AK098774 AK130774 AK290936
    RefSeq transcript (Entrez)NM_001010850 NM_001170634 NM_001170937 NM_004960
    RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NG_012889 NT_010393 NW_001838236 NW_004929400
    Consensus coding sequences : CCDS (NCBI)FUS
    Cluster EST : UnigeneHs.46894 [ NCBI ]
    CGAP (NCI)Hs.46894
    Alternative Splicing : Fast-db (Paris)GSHG0011132
    Alternative Splicing GalleryENSG00000089280
    Gene ExpressionFUS [ NCBI-GEO ]     FUS [ SEEK ]   FUS [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP35637 (Uniprot)
    NextProtP35637  [Medical]
    With graphics : InterProP35637
    Splice isoforms : SwissVarP35637 (Swissvar)
    Domaine pattern : Prosite (Expaxy)RRM (PS50102)    ZF_RANBP2_1 (PS01358)    ZF_RANBP2_2 (PS50199)   
    Domains : Interpro (EBI)Nucleotide-bd_a/b_plait    RRM_dom    Znf_RanBP2   
    Related proteins : CluSTrP35637
    Domain families : Pfam (Sanger)RRM_1 (PF00076)    zf-RanBP (PF00641)   
    Domain families : Pfam (NCBI)pfam00076    pfam00641   
    Domain families : Smart (EMBL)RRM (SM00360)  ZnF_RBZ (SM00547)  
    DMDM Disease mutations2521
    Blocks (Seattle)P35637
    PDB (SRS)2LA6    2LCW    4FDD   
    PDB (PDBSum)2LA6    2LCW    4FDD   
    PDB (IMB)2LA6    2LCW    4FDD   
    PDB (RSDB)2LA6    2LCW    4FDD   
    Human Protein AtlasENSG00000089280
    Peptide AtlasP35637
    HPRD00660
    IPIIPI00221354   IPI00854677   IPI00909890   IPI00260715   IPI00645208   
    Protein Interaction databases
    DIP (DOE-UCLA)P35637
    IntAct (EBI)P35637
    FunCoupENSG00000089280
    BioGRIDFUS
    InParanoidP35637
    Interologous Interaction database P35637
    IntegromeDBFUS
    STRING (EMBL)FUS
    Ontologies - Pathways
    Ontology : AmiGOnucleotide binding  mRNA splicing, via spliceosome  DNA binding  RNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytoplasm  cell death  zinc ion binding  RNA splicing  gene expression  identical protein binding  
    Ontology : EGO-EBInucleotide binding  mRNA splicing, via spliceosome  DNA binding  RNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytoplasm  cell death  zinc ion binding  RNA splicing  gene expression  identical protein binding  
    Pathways : KEGGTranscriptional misregulation in cancer   
    REACTOMEFUS
    Protein Interaction DatabaseFUS
    Wikipedia pathwaysFUS
    Gene fusion - rearrangments
    Rearrangement : COSMICCREB3L2 [7q33]  -  FUS [16p11.2]
    Rearrangement : COSMICDDIT3 [12q13.3]  -  FUS [16p11.2]
    Rearrangement : COSMICFUS [16p11.2]  -  ATF1 [12q13.12]
    Rearrangement : COSMICFUS [16p11.2]  -  CREB3L1 [11p11.2]
    Rearrangement : COSMICFUS [16p11.2]  -  CREB3L2 [7q33]
    Rearrangement : COSMICFUS [16p11.2]  -  DDIT3 [12q13.3]
    Rearrangement : COSMICFUS [16p11.2]  -  ERG [21q22.2]
    Rearrangement : COSMICFUS [16p11.2]  -  FEV [2q35]
    Rearrangement : TICdbATF1 [12q13.12]  -  FUS [16p11.2]
    Rearrangement : TICdbCREB3L1 [11p11.2]  -  FUS [16p11.2]
    Rearrangement : TICdbCREB3L2 [7q33]  -  FUS [16p11.2]
    Rearrangement : TICdbDDIT3 [12q13.3]  -  FUS [16p11.2]
    Rearrangement : TICdbERG [21q22.2]  -  FUS [16p11.2]
    Rearrangement : TICdbFEV [2q35]  -  FUS [16p11.2]
    Rearrangement : TICdbFUS [16p11.2]  -  ATF1 [12q13.12]
    Rearrangement : TICdbFUS [16p11.2]  -  CREB3L1 [11p11.2]
    Rearrangement : TICdbFUS [16p11.2]  -  CREB3L2 [7q33]
    Rearrangement : TICdbFUS [16p11.2]  -  DDIT3 [12q13.3]
    Rearrangement : TICdbFUS [16p11.2]  -  ERG [21q22.2]
    Rearrangement : TICdbFUS [16p11.2]  -  FEV [2q35]
    Rearrangement : TICdbFUS [16p11.2]  -  FUS [16p11.2]
    Rearrangement : TICdbFUS [16p11.2]  -  FUS [16p11.2]
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)FUS
    SNP (GeneSNP Utah)FUS
    SNP : HGBaseFUS
    Genetic variants : HAPMAPFUS
    1000_GenomesFUS 
    ICGC programENSG00000089280 
    Cancer Gene: CensusFUS 
    Somatic Mutations in Cancer : COSMICFUS 
    CONAN: Copy Number AnalysisFUS 
    Mutations and Diseases : HGMDFUS
    OMIM137070    608030    614782   
    GENETestsFUS
    Disease Genetic AssociationFUS
    Huge Navigator FUS [HugePedia]  FUS [HugeCancerGEM]
    Genomic VariantsFUS  FUS [DGVbeta]
    Exome VariantFUS
    dbVarFUS
    ClinVarFUS
    snp3D : Map Gene to Disease2521
    General knowledge
    Homologs : HomoloGeneFUS
    Homology/Alignments : Family Browser (UCSC)FUS
    Phylogenetic Trees/Animal Genes : TreeFamFUS
    Chemical/Protein Interactions : CTD2521
    Chemical/Pharm GKB GenePA28425
    Clinical trialFUS
    Cancer Resource (Charite)ENSG00000089280
    Other databases
    Probes
    Litterature
    PubMed216 Pubmed reference(s) in Entrez
    CoreMineFUS
    iHOPFUS

    Bibliography

    Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.
    Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR
    Nature. 2007 ; 446 (7137) : 758-764.
    PMID 17344859
     
    Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).
    Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willn H, Rydholm A, Mitelman F
    Genes, chromosomes & cancer. 1992 ; 5 (4) : 278-285.
    PMID 1283316
     
    Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.
    Crozat A, Aman P, Mandahl N, Ron D
    Nature. 1993 ; 363 (6430) : 640-644.
    PMID 8510758
     
    Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.
    Rabbitts TH, Forster A, Larson R, Nathan P
    Nature genetics. 1993 ; 4 (2) : 175-180.
    PMID 7503811
     
    An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.
    Ichikawa H, Shimizu K, Hayashi Y, Ohki M
    Cancer research. 1994 ; 54 (11) : 2865-2868.
    PMID 8187069
     
    TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain.
    Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES
    Oncogene. 1994 ; 9 (12) : 3717-3729.
    PMID 7970732
     
    Transcriptional activation by TAL1 and FUS-CHOP proteins expressed in acute malignancies as a result of chromosomal abnormalities.
    Snchez-Garca I, Rabbitts TH
    Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (17) : 7869-7873.
    PMID 8058726
     
    Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry.
    Calvio C, Neubauer G, Mann M, Lamond AI
    RNA (New York, N.Y.). 1995 ; 1 (7) : 724-733.
    PMID 7585257
     
    Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.
    Knight JC, Renwick PJ, Cin PD, Van den Berghe H, Fletcher CD
    Cancer research. 1995 ; 55 (1) : 24-27.
    PMID 7805034
     
    Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.
    Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Hglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F
    Genomics. 1996 ; 37 (1) : 1-8.
    PMID 8921363
     
    Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript.
    Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M, Hayashi Y
    Blood. 1997 ; 90 (3) : 1192-1199.
    PMID 9242552
     
    Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.
    Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N, Aman P
    Oncogene. 1997 ; 15 (11) : 1357-1362.
    PMID 9315104
     
    Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.
    Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N, Aman P
    Oncogene. 1997 ; 15 (11) : 1357-1362.
    PMID 9315104
     
    TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling.
    Zinszner H, Sok J, Immanuel D, Yin Y, Ron D
    Journal of cell science. 1997 ; 110 ( Pt 15) : 1741-1750.
    PMID 9264461
     
    Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes.
    Morohoshi F, Ootsuka Y, Arai K, Ichikawa H, Mitani S, Munakata N, Ohki M
    Gene. 1998 ; 221 (2) : 191-198.
    PMID 9795213
     
    TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis.
    Perrotti D, Bonatti S, Trotta R, Martinez R, Skorski T, Salomoni P, Grassilli E, Lozzo RV, Cooper DR, Calabretta B
    The EMBO journal. 1998 ; 17 (15) : 4442-4455.
    PMID 9687511
     
    Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS).
    Ichikawa H, Shimizu K, Katsu R, Ohki M
    Molecular and cellular biology. 1999 ; 19 (11) : 7639-7650.
    PMID 10523652
     
    Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death.
    Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley HE
    Nature genetics. 2000 ; 24 (2) : 175-179.
    PMID 10655065
     
    Male sterility and enhanced radiation sensitivity in TLS(-/-) mice.
    Kuroda M, Sok J, Webb L, Baechtold H, Urano F, Yin Y, Chung P, de Rooij DG, Akhmedov A, Ashley T, Ron D
    The EMBO journal. 2000 ; 19 (3) : 453-462.
    PMID 10654943
     
    A novel FUS/CHOP chimera in myxoid liposarcoma.
    Panagopoulos I, Mertens F, Isaksson M, Mandahl N
    Biochemical and biophysical research communications. 2000 ; 279 (3) : 838-845.
    PMID 11162437
     
    The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice.
    Prez-Losada J, Pintado B, Gutirrez-Adn A, Flores T, Baares-Gonzlez B, del Campo JC, Martn-Martn JF, Battaner E, Snchez-Garca I
    Oncogene. 2000 ; 19 (20) : 2413-2422.
    PMID 10828883
     
    Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma.
    Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Prez-Mancera PA, Pintado B, Flores T, Battaner E, Snchez-Garia I
    Oncogene. 2000 ; 19 (52) : 6015-6022.
    PMID 11146553
     
    Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.
    Waters BL, Panagopoulos I, Allen EF
    Cancer genetics and cytogenetics. 2000 ; 121 (2) : 109-116.
    PMID 11063792
     
    Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.
    Prez-Mancera PA, Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Flores T, Battaner E, Gutirrez-Adn A, Pintado B, Snchez-Garca I
    Oncogene. 2002 ; 21 (11) : 1679-1684.
    PMID 11896599
     
    Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.
    Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, Mandahl N, Panagopoulos I
    Human molecular genetics. 2003 ; 12 (18) : 2349-2358.
    PMID 12915480
     
    The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma.
    Panagopoulos I, Storlazzi CT, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosj O, Rydholm A, Isaksson M, Mandahl N, Mertens F
    Genes, chromosomes & cancer. 2004 ; 40 (3) : 218-228.
    PMID 15139001
     
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    Contributor(s)

    Written07-2004PA Pérez-Mancera, Isidro Sánchez-Garía
    Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain

    Citation

    This paper should be referenced as such :
    Pérez-Mancera PA, Sánchez-Garía I . FUS (fusion involved in t (12;16) in malignant liposarcoma). Atlas Genet Cytogenet Oncol Haematol. July 2004 .
    URL : http://AtlasGeneticsOncology.org/Genes/FUSID44.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/38109/1/07-2004-FUSID44.pdf   [ Bibliographic record ]

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