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FANCA (Fanconi anaemia complementation group A)

Identity

Other namesFACA
FAA
FA1
HGNC FANCA
Location 16q24.3
Location_base_pair Starts at 88331460 and ends at 88410566 bp from pter ( according to hg18-Mar_2006).

DNA/RNA

Description 43 exons spanning 80 kb; 4365 bp open reading frame
Transcription 5.5 kb mRNA

Protein

Description 1455 amino acids; 163 kDa; 2 nuclear localisation signals (NLS) consensus sequences in N-terminus and a leucine zipper in 1069-1090, none proven to functional as such; FANCA is normally phosphorylated
Expression wide: brain, placenta, testis,tonsils (mRNA); in mice: protein expression predominant in lymphoid organs, testis, ovary.
Localisation both cytoplasmic and nuclear
Function part of the FA complex with FANCC, FANCE, FANCF, and FANCG; this complex is only found in the nucleus.
  • FANCA and FANCG form a complex in the cytoplasm, through a N-term FANCA (involving the nuclear localization signal) - FANCG interaction; FANCC join the complex; phosphorylation of FANCA would induce its translocation into the nucleus.This FA complex translocates into the nucleus, where FANCE and FANCF are present; FANCE and FANCF join the complex. The FA complex subsequently interacts with FANCD2 by monoubiquitination of FANCD2 during S phase or following DNA damage. Activated (ubiquinated ) FANCD2, downstream in the FA pathway, will then interact with other proteins involved in DNA repair, possibly BRCA1; after DNA repair, FANCD2 return to the non-ubiquinated form.
    • Homology no known homology or functional motifs

    Mutations

    Germinal various nucleotide substitutions, deletions, or insertions have been described. Over 90% of the mutations are private, with about 30% being relatively large deletions. Founder mutations have been described in South Africa.

    Implicated in

    Entity Fanconi anaemia (FA); FANCA is implicated in the FA complementation group A; it represents about 70% of FA cases
    Disease Fanconi anaemia is a chromosome instability syndrome/cancer prone disease (at risk of leukaemia and squamous cell carcinoma)
    Prognosis
  • Fanconi anaemia's prognosis is poor; mean survival is 20 years: patients die of bone marrow failure (infections, haemorrhages), leukaemia, or solid cancer.
  • It has recently been shown that significant phenotypic differences were found between the various complementation groups. In FA group A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. Patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention.
    • Cytogenetics Spontaneously enhanced chromatid-type aberrations (breaks, gaps, interchanges; increased rate of breaks compared to control, when induced by specific clastogens known as DNA cross-linking agents (e.g. mitomycin C, diepoxybutane).
      

    External links

    Nomenclature
    HGNCFANCA   3582
    Entrez_GeneFANCA  2175  Fanconi anemia, complementation group A
    Cards
    AtlasFA1ID102
    GeneCardsFANCA
    EnsemblENSG00000187741 [Gene_View]  FANCA [Vega]
    GenatlasFANCA
    Genomic and cartography
    GoldenPathFANCA  -  16q24.3   chr16:88331460-88410566 -  16q24.3   [Description]    (hg18-Mar_2006)
    EnsemblFANCA - 16q24.3 [CytoView]
    NCBIMapview
    OMIM227650 Disease map [OMIM]
    OMIM607139 Disease map [OMIM]
    HomoloGeneFANCA
    Gene and transcription
    GenbankAK299282 [ ENTREZ ]
    GenbankBC008979 [ ENTREZ ]
    GenbankBC022498 [ ENTREZ ]
    GenbankBC064540 [ ENTREZ ]
    GenbankBC120978 [ ENTREZ ]
    RefSeqNM_000135 [ SRS ]    NM_000135 [ ENTREZ ]
    RefSeqNM_001018112 [ SRS ]    NM_001018112 [ ENTREZ ]
    RefSeqAC_000059 [ SRS ]    AC_000059 [ ENTREZ ]
    RefSeqAC_000148 [ SRS ]    AC_000148 [ ENTREZ ]
    RefSeqNC_000016 [ SRS ]    NC_000016 [ ENTREZ ]
    RefSeqNT_010542 [ SRS ]    NT_010542 [ ENTREZ ]
    RefSeqNW_001838336 [ SRS ]    NW_001838336 [ ENTREZ ]
    RefSeqNW_926561 [ SRS ]    NW_926561 [ ENTREZ ]
    CCDSFANCA CCDS - NCBI
    AceViewFANCA AceView - NCBI
    UnigeneHs.567267 [ SRS ]    Hs.567267 [ NCBI ]
    Fast-db12658 (alternative variants)
    Protein : pattern, domain, 3D structure
    SwissProtO15360 [ SRS]    O15360 [ EXPASY ]     O15360 [ INTERPRO ]     O15360 [ UNIPROT ] O15360 [ VarSplice FASTA ]
    InterproIPR003516 Fanconia [ SRS ]    IPR003516 Fanconia [ EBI ]
    CluSTrO15360
    PfamPF03511 Fanconi_A [ SRS ]    PF03511 Fanconi_A [ Sanger ]    pfam03511 [ NCBI-CDD ]
    BlocksO15360
    HPRD06186
    Protein Interaction databases
    DIPO15360
    IntActO15360
    Polymorphism : SNP, mutations, diseases
    OMIM227650    [ map ]   
    OMIM607139    [ map ]   
    GENETests227650
    GENETests607139
    SNPFANCA [dbSNP-NCBI]  
    SNPNM_000135 [SNP-NCI]  
    SNPNM_001018112 [SNP-NCI]  
    SNPFANCA [GeneSNPs - Utah]  FANCA] [HGBASE - SRS]
    HAPMAPFANCA [HAPMAP]  
    COSMICFANCA [Somatic mutation (COSMIC-CGP-Sanger)]  
    HGMDFANCA
    Genetic AssociationFANCA
    CDC HuGEFANCA
    General knowledge
    Family BrowserFANCA [UCSC Family Browser]
    SOURCENM_000135
    SOURCENM_001018112
    SMDHs.567267
    SAGEHs.567267
    GOprotein binding [Amigo]  protein binding
    GOnucleus [Amigo]  nucleus
    GOcytoplasm [Amigo]  cytoplasm
    GODNA repair [Amigo]  DNA repair
    GOprotein complex assembly [Amigo]  protein complex assembly
    BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility    [Genes]
    BIOCARTABRCA1-dependent Ub-ligase activity    [Genes]
    PubGeneFANCA
    TreeFamFANCA
    CTD2175 [Comparative ToxicoGenomics Database]
    Other databases
    Other databaseFanconi Anemia Mutation Database
    Probes
    ProbeFANCA Related clones (RZPD - Berlin)
    PubMed
    PubMed74 Pubmed reference(s) in Entrez

    Bibliography

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    Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.
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    Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain.
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    A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation.
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    Characterization of regions functional in the nuclear localization of the Fanconi anemia group A protein.
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    Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex.
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    PMID 10551855
     
    High frequency of large intragenic deletions in the Fanconi anemia group A gene.
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    American journal of human genetics. 1999 ; 65 (5) : 1330-1341.
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    A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA.
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    Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.
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    Intracellular localization of the Fanconi anemia complementation group A protein.
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    PMID 10364463
     
    Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein.
    Balta G, de Winter JP, Kayserili H, Pronk JC, Joenje H
    Human mutation. 2000 ; 15 (6) : page 578.
    PMID 10862090
     
    Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
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    Blood. 2000 ; 96 (13) : 4064-4070.
    PMID 11110674
     
    The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex.
    Garcia-Higuera I, Kuang Y, Denham J, D'Andrea AD
    Blood. 2000 ; 96 (9) : 3224-3230.
    PMID 11050007
     
    Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis.
    Huber PA, Medhurst AL, Youssoufian H, Mathew CG
    Biochemical and biophysical research communications. 2000 ; 268 (1) : 73-77.
    PMID 10652215
     
    Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity.
    Kuang Y, Garcia-Higuera I, Moran A, Mondoux M, Digweed M, D'Andrea AD
    Blood. 2000 ; 96 (5) : 1625-1632.
    PMID 10961856
     
    Cloning and characterization of murine fanconi anemia group A gene: Fanca protein is expressed in lymphoid tissues, testis, and ovary.
    van de Vrugt HJ, Cheng NC, de Vries Y, Rooimans MA, de Groot J, Scheper RJ, Zhi Y, Hoatlin ME, Joenje H, Arwert F
    Mammalian genome : official journal of the International Mammalian Genome Society. 2000 ; 11 (4) : 326-331.
    PMID 10754110
     
    The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.
    de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H
    Human molecular genetics. 2000 ; 9 (18) : 2665-2674.
    PMID 11063725
     
    Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.
    Wong JC, Alon N, Norga K, Kruyt FA, Youssoufian H, Buchwald M
    Genomics. 2000 ; 67 (3) : 273-283.
    PMID 10936049
     
    Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment.
    Futaki M, Watanabe S, Kajigaya S, Liu JM
    Biochemical and biophysical research communications. 2001 ; 281 (2) : 347-351.
    PMID 11181053
     
    Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.
    Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD
    Molecular cell. 2001 ; 7 (2) : 249-262.
    PMID 11239454
     
    Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells.
    Gregory JJ Jr, Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, Steffenhagen A, Hirsch B, Auerbach AD
    Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (5) : 2532-2537.
    PMID 11226273
     
    Fanconi anemia and DNA repair.
    Grompe M, D'Andrea A
    Human molecular genetics. 2001 ; 10 (20) : 2253-2259.
    PMID 11673408
     
    Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links.
    McMahon LW, Sangerman J, Goodman SR, Kumaresan K, Lambert MW
    Biochemistry. 2001 ; 40 (24) : 7025-7034.
    PMID 11401546
     
    Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway.
    Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG
    Human molecular genetics. 2001 ; 10 (4) : 423-429.
    PMID 11157805
     
    Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.
    Otsuki T, Furukawa Y, Ikeda K, Endo H, Yamashita T, Shinohara A, Iwamatsu A, Ozawa K, Liu JM
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    PMID 11726552
     
    Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner.
    Qiao F, Moss A, Kupfer GM
    The Journal of biological chemistry. 2001 ; 276 (26) : 23391-23396.
    PMID 11297559
     
    Functional analysis of the putative peroxidase domain of FANCA, the Fanconi anemia complementation group A protein.
    Ren J, Youssoufian H
    Molecular genetics and metabolism. 2001 ; 72 (1) : 54-60.
    PMID 11161829
     
    A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA.
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    PMID 11530803
     
    Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.
    Callˆ©n E, Samper E, Ramˆ‚rez MJ, Creus A, Marcos R, Ortega JJ, Olivˆ© T, Badell I, Blasco MA, Surrallˆ©s J
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    PMID 11854176
     
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    Contributor(s)

    Written04-1998Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
    Updated12-2001Hans Joenje
    Department of Clinical Genetics and Human Genetics VU University Medical Center Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands
    Updated06-2002Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

    Citation

    This paper should be referenced as such :
    Huret JL . FANCA (Fanconi anaemia complementation group A). Atlas Genet Cytogenet Oncol Haematol. April 1998 .
    URL : http://AtlasGeneticsOncology.org/Genes/FA1ID102.html
    Joenje H . FANCA (Fanconi anaemia complementation group A). Atlas Genet Cytogenet Oncol Haematol. December 2001 .
    URL : http://AtlasGeneticsOncology.org/Genes/FA1ID102.html
    Huret JL . FANCA (Fanconi anaemia complementation group A). Atlas Genet Cytogenet Oncol Haematol. June 2002 .
    URL : http://AtlasGeneticsOncology.org/Genes/FA1ID102.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Nov 27 13:22:41 2008

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