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SEPT9 (MLL septin-like fusion)

Identity

Other namesMSF (MLL septin-like fusion)
MSF1
AF17q25 (ALL1 fused gene from chromosome 17q25)
KIAA0991
PNUTL4
HGNC (Hugo) SEPT9
LocusID (NCBI) 10801
Location 17q25.2
Location_base_pair Starts at 75277492 and ends at 75496678 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Maps to chromosome 17 interval D17S785-D17S836

DNA/RNA

 
  Genomic structure of published MSF alternatively spliced transcripts. Boxes indicate exons with coding regions colored in yellow and are drawn to scale. Exons are tentatively positioned in relative genomic order with overlapping exons indicating identical sequences. Translation start sites are indicated by an arrows and proceeds centromere to telomere on 17q25.
Transcription MSF exhibits 5' and 3' alternative splicing. The variable exons encode different translational start and stop sequences and are spliced on to a core of 8 coding exons. It is unclear the splicing mechanism between exon 12 and exon 13 subsets as splicing does not occur at traditional GT/AG conserved sequences. Multiple reports are consistent in observing expression of an approximately 4.0 kb transcript in all fetal and adult tissues. Additional transcripts at approximately 3.0 kb and 1.7 kb are variably reported and may reflect differences in probe sequence and experimental conditions between laboratories. MSF spans approximately 260 kb of DNA based on NotI PFGE mapping.

Protein

 
  Structure of MSF protein isoforms. Coding regions are indicated between red arrows. Like colors denote identical sequences. Domains are marked by light purple boxes for xylose isomerase, orange for polybasic, and red for GTPase. Gaps indicate missing sequences in that variant. References for a-c match those in the exon/intron figure. Figure is not drawn to scale.
Description Alternative transcript splicing results in translation of multiple MSF isoforms with distinct amino-and carboxy-termini. MSF-B and MSF-C proteins are identical and are sub-sequences within the other larger isoforms. All isoforms contain a GTPase domain, a xylose isomerase domain of unknown mammalian function but previously identified for sugar interconversion in some microorganisms, and a semi-conserved polybasic domain shown in the septin H5 to be necessary for membrane phospholipid binding.
Expression The MSF protein is believed to be widely expressed based on ubiquitous adult and fetal transcript expression, although individual isoforms may have tissue specific expression.
Localisation The MSF protein, like other septin family members, contains no subcellular localization signals and is thought to be largely cytoplasmic. Despite this, mammalian septins have been found in the mitochondria, in the nucleus, and associated with the plasma membrane and brain synaptic vesicles.
Function Although little information is currently available for MSF itself, research on other members of this highly conserved septin GTPase subfamily provides insight into potential functional roles of MSF. The original family members, Saccharomyces cerevisiae CDC3, CDC10, CDC11, and CDC12, were identified by rescue of temperature sensitive mutants exhibiting the near identical phenotypes of cell-cycle arrest, elongated bud growth, and impaired cytokinesis. They localize to the cleavage furrow, co-immunoprecipitate, and polymerize into filaments. Septins have since been broadly identified in most eukaryotic organisms except for plants. Despite the distinct mechanistic differences in cell division between yeast and animal cells, animal septins similarly localize to the contractile ring and polymerize into filaments. These filaments are composed of homo- and heteromultimers of septins, require GTP hydrolysis to assemble, and interact with anillin, an actin binding protein found at the contractile ring during cytokinesis. Like yeast, multinucleated cells are produced when septins are mutated. Isolation of the yeast septins SPR3 and SPR28 with roles in sporulation, however, provided the initial evidence for other septin functions in addition to cytokinesis. Binding of Cdc12p to the mating hormone induced Afr1p and of Cdc10p to the chitin associated Bni4p, suggests roles for septins in determining the site of fusion in yeast in chitin deposition, respectively. Identification of interacting proteins implicates yeast septins in cell cycle regulation based on binding to the mitosis-inducing protein kinase Gin4p (Cdc3p, Cdc10p, Cdc11p, Cdc12p, Sep7p), to the mitotic checkpoint Bub2p (Cdc3p), and to the cyclin Clb2p degrading polo kinase Cdc5p (Cdc11p and Cdc12p). In addition, yeast septins Cdc3p and Cdc11p are cell-cycle specific substrates for conjugation to the ubiquitin-related SUMOp. Of the mammalian septins, the ARTS protein translocates from the mitochondria to the nucleus and enhances cell death in response to TGF-b. CDC10, NEDD5, H5, E-septin and Septin 6 associate with the rat SEC6/SEC8 multimer, a key conserved complex in targeting exocytosis at the plasma membrane. H5 binds in a GDP-associated form to membrane phospholipids through a polybasic domain, and CDCREL-1 and NEDD5 co-purify with brain synaptic vesicles and interact with syntaxin, a key protein for vesicle-membrane fusion. Given that cytokinesis is one highly conserved role of septins, this later observation is somewhat unexpected given that brain typically exhibits minimal cell division activity. However, further evidence for septin roles in neuronal development are suggested by the degradation of CDCREL-1 after ubiquitination by the Parkinson's disease gene parkin and by the association of NEDD5, H5, and DIFF6 septins with neurofibrillary tangles in Alzheimer's disease. Thus, these data present a myriad of functions for members of the septin protein family that can be more broadly grouped into integral roles in cell cycle regulation, signal transduction, and protein/vesicle trafficking through cytoskeletal scaffolding. These functions are probably partially determined by tissue- and temporal-specific expression levels of individual septins and their isoforms and provide a framework for further characterization of MSF.
Homology MSF exhibits protein homology (% identity/% similarity) to the following orthologous septin family members: S. cerevisiae CDC10 47%/67%, D. melanogaster Pnut 39%/57%, R. norvegicus E-septin short 96%/97%, M. musculus SINT1 96%/98%, and to the following human septins also found as fusion proteins with MLL in leukemia patients: hCDCRel-1 in 22q11 45%/66%, Septin 6/KIAA0128 in Xq24 43%/66%.

Implicated in

Entity t(11;17)(q23;q25) acute non lymphocytic leukemia (ANLL) --> MLL - MSF
Disease de novo and treatment related leukemia
Prognosis poor
Hybrid/Mutated Gene in-frame transcript joining the 5' of MLL through exon 5 to MSF at the start of exon 3 through the 3' terminus. A reciprocal transcript was amplified in one patient joining the 5' of MSF through exon 1 to exon 7 of MLL but was out of frame. No 5' MSF-3' MLL transcript was amplified in another patient.
Abnormal Protein fusion protein of an amino protein terminus MLL, including the nuclear localization signal, the A-T hook DNA binding domain, and the DNA methyltransferase-like DNA binding domain, and a carboxy terminus MSF, including the xylose isomerase, the polybasic and GTPase domains. Lost from the carboxy terminus of MLL is the PHD zinc finger protein-protein interaction domain and the SET domain thought to regulate gene expression through chromatin remodeling. It has been suggested that MLL is the sole clinical culprit in leukemias with 11q23 rearrangements as it is fused to a wide variety of other genes. However, these translocations produce an in-frame fusion protein, suggesting selection for a translatable protein. In addition, the general observations of phenotypic variability with different translocations, including patient age, leukemia types, and prognostic outcomes, provide further evidence that proteins at the varying reciprocally translocated chromosomes are essential contributors to the pathogenesis of leukemia. Thus, speculation on the contributions of MLL-MSF fusion protein expression to haematopoetic cellular transformation would include potential mislocalization of MSF from the cytoplasm to the nucleus, aberrant expression of MLL target proteins and altered activation of MSF GTPase signaling pathways.
Oncogenesis In addition to the involvement of various septins in leukemia patients, the MSF mouse ortholog SINT1 was identified by virtue of its presence at a provirus insertion site in SL3-3 MLV-induced lymphomas suggesting a subgroup of septins may play a more specific role in leukemogenesis.
  

To be noted

MSF maps within a 300 kb candidate breast and ovarian tumor suppressor gene region on 17q25 previously defined by allelic imbalance studies in matched normal and tumor samples. Given the role GTPases have been shown to play in cellular proliferation and the proposed role of the highly conserved septin family in cell cycle regulation, MSF is an obvious candidate gene. Preliminary analysis of the MSF coding region in breast and ovarian tumors have only revealed polymorphic variants of no proven clinical relevence.

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias t0817q24q22ID1494 t1119q23p13ID1540

External links

Nomenclature
HGNC (Hugo)SEPT9   7323
Cards
AtlasMSFID208
Entrez_Gene (NCBI)SEPT9  10801  septin 9
GeneCards (Weizmann)SEPT9
Ensembl (Hinxton)ENSG00000184640 [Gene_View]  chr17:75277492-75496678 [Contig_View]  SEPT9 [Vega]
ICGC DataPortalENSG00000184640
cBioPortalSEPT9
AceView (NCBI)SEPT9
Genatlas (Paris)SEPT9
WikiGenes10801
SOURCE (Princeton)NM_001113491 NM_001113492 NM_001113493 NM_001113494 NM_001113495 NM_001113496 NM_001293695 NM_001293696 NM_001293697 NM_001293698 NM_006640
Genomic and cartography
GoldenPath (UCSC)SEPT9  -  17q25.2   chr17:75277492-75496678 +  17q25.3   [Description]    (hg19-Feb_2009)
EnsemblSEPT9 - 17q25.3 [CytoView]
Mapping of homologs : NCBISEPT9 [Mapview]
OMIM162100   604061   
Gene and transcription
Genbank (Entrez)AA523782 AB023208 AF123052 AF142408 AF142569
RefSeq transcript (Entrez)NM_001113491 NM_001113492 NM_001113493 NM_001113494 NM_001113495 NM_001113496 NM_001293695 NM_001293696 NM_001293697 NM_001293698 NM_006640
RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NG_011683 NT_010783 NW_001838454 NW_001838455 NW_003315955 NW_004929407
Consensus coding sequences : CCDS (NCBI)SEPT9
Cluster EST : UnigeneHs.440932 [ NCBI ]
CGAP (NCI)Hs.440932
Alternative Splicing : Fast-db (Paris)GSHG0012848
Alternative Splicing GalleryENSG00000184640
Gene ExpressionSEPT9 [ NCBI-GEO ]     SEPT9 [ SEEK ]   SEPT9 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UHD8 (Uniprot)
NextProtQ9UHD8  [Medical]
With graphics : InterProQ9UHD8
Splice isoforms : SwissVarQ9UHD8 (Swissvar)
Domains : Interpro (EBI)Cell_div_GTP-bd [organisation]   P-loop_NTPase [organisation]  
Related proteins : CluSTrQ9UHD8
Domain families : Pfam (Sanger)Septin (PF00735)   
Domain families : Pfam (NCBI)pfam00735   
DMDM Disease mutations10801
Blocks (Seattle)Q9UHD8
Human Protein AtlasENSG00000184640 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ9UHD8
HPRD10360
IPIIPI00871679   IPI00030173   IPI01010880   IPI00784614   IPI00455033   IPI00784808   IPI00883870   IPI00784835   IPI00784936   
Protein Interaction databases
DIP (DOE-UCLA)Q9UHD8
IntAct (EBI)Q9UHD8
FunCoupENSG00000184640
BioGRIDSEPT9
InParanoidQ9UHD8
Interologous Interaction database Q9UHD8
IntegromeDBSEPT9
STRING (EMBL)SEPT9
Ontologies - Pathways
Ontology : AmiGOstress fiber  GTPase activity  protein binding  GTP binding  cytoplasm  microtubule  GTP catabolic process  cell cycle  actin cytoskeleton  perinuclear region of cytoplasm  protein heterooligomerization  cell division  
Ontology : EGO-EBIstress fiber  GTPase activity  protein binding  GTP binding  cytoplasm  microtubule  GTP catabolic process  cell cycle  actin cytoskeleton  perinuclear region of cytoplasm  protein heterooligomerization  cell division  
Pathways : KEGGBacterial invasion of epithelial cells   
Protein Interaction DatabaseSEPT9
Wikipedia pathwaysSEPT9
Gene fusion - rearrangments
Rearrangement : TICdbKMT2A [11q23.3]  -  SEPT9 [Xp11.23]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SEPT9
snp3D : Map Gene to Disease10801
SNP (GeneSNP Utah)SEPT9
SNP : HGBaseSEPT9
Genetic variants : HAPMAPSEPT9
Exome VariantSEPT9
1000_GenomesSEPT9 
ICGC programENSG00000184640 
Cancer Gene: CensusSEPT9 
Somatic Mutations in Cancer : COSMICSEPT9 
CONAN: Copy Number AnalysisSEPT9 
Mutations and Diseases : HGMDSEPT9
Genomic VariantsSEPT9  SEPT9 [DGVbeta]
dbVarSEPT9
ClinVarSEPT9
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM162100    604061   
MedgenSEPT9
GENETestsSEPT9
Disease Genetic AssociationSEPT9
Huge Navigator SEPT9 [HugePedia]  SEPT9 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneSEPT9
Homology/Alignments : Family Browser (UCSC)SEPT9
Phylogenetic Trees/Animal Genes : TreeFamSEPT9
Chemical/Protein Interactions : CTD10801
Chemical/Pharm GKB GenePA31132
Clinical trialSEPT9
Cancer Resource (Charite)ENSG00000184640
Other databases
Probes
Litterature
PubMed93 Pubmed reference(s) in Entrez
CoreMineSEPT9
iHOPSEPT9
OncoSearchSEPT9

Bibliography

MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25).
Osaka M, Rowley JD, Zeleznik-Le NJ
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (11) : 6428-6433.
PMID 10339604
 
AF17q25, a putative septin family gene, fuses the MLL gene in acute myeloid leukemia with t(11;17)(q23;q25).
Taki T, Ohnishi H, Shinohara K, Sako M, Bessho F, Yanagisawa M, Hayashi Y
Cancer research. 1999 ; 59 (17) : 4261-4265.
PMID 10485469
 
Genomic and expression analyses of alternatively spliced transcripts of the MLL septin-like fusion gene (MSF) that map to a 17q25 region of loss in breast and ovarian tumors.
Kalikin LM, Sims HL, Petty EM
Genomics. 2000 ; 63 (2) : 165-172.
PMID 10673329
 
Isolation and mapping of a human septin gene to a region on chromosome 17q, commonly deleted in sporadic epithelial ovarian tumors.
Russell SE, McIlhatton MA, Burrows JF, Donaghy PG, Chanduloy S, Petty EM, Kalikin LM, Church SW, McIlroy S, Harkin DP, Keilty GW, Cranston AN, Weissenbach J, Hickey I, Johnston PG
Cancer research. 2000 ; 60 (17) : 4729-4734.
PMID 10987277
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2000Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated08-2001Linda M. Kalikin, Elizabeth M. Petty
Research Investigator, Department of Internal Medicine, The University of Michigan, USA

Citation

This paper should be referenced as such :
Kalikin, LM ; Petty, EM
MSF (MLL septin-like fusion)
Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):259-162.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Kalikin, LM ; Petty, EM. MSF (MLL septin-like fusion). Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):259-162.
http://documents.irevues.inist.fr/bitstream/2042/37780/1/08-2001-MSFID208.pdf
URL : http://AtlasGeneticsOncology.org/Genes/MSFID208.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Jul 26 15:13:40 CEST 2014

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