FANCA (Fanconi anaemia complementation group A)

Identity

Other names	FACA
	FAA
	FA1
Hugo	FANCA
Location	16q24.3

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
Hugo	FANCA
GDB	FANCA
Entrez_Gene	FANCA  2175  Fanconi anemia, complementation group A
	Cards
Atlas	FA1ID102
GeneCards	FANCA
Ensembl	FANCA [Search_View]   ENSG00000187741 [Gene_View]
Genatlas	FANCA
GeneLynx	FANCA
eGenome	FANCA
euGene	2175
	Genomic and cartography
GoldenPath	FANCA  -  16q24.3   chr16:88392268-88410566 -  16q24.3   [Description]    (hg18-Mar_2006)
Ensembl	FANCA - 16q24.3 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	FANCA
	Gene and transcription
Genbank	BC008979 [ ENTREZ ]
Genbank	BC022498 [ ENTREZ ]
Genbank	BC064540 [ ENTREZ ]
Genbank	BC120978 [ ENTREZ ]
Genbank	BC120979 [ ENTREZ ]
RefSeq	NM_000135 [ SRS ]    NM_000135 [ ENTREZ ]
RefSeq	NM_001018112 [ SRS ]    NM_001018112 [ ENTREZ ]
RefSeq	AC_000059 [ SRS ]    AC_000059 [ ENTREZ ]
RefSeq	NC_000016 [ SRS ]    NC_000016 [ ENTREZ ]
RefSeq	NT_010542 [ SRS ]    NT_010542 [ ENTREZ ]
RefSeq	NW_926561 [ SRS ]    NW_926561 [ ENTREZ ]
AceView	FANCA AceView - NCBI
Unigene	Hs.567267 [ SRS ]    Hs.567267 [ NCBI ]     HS567267 [ spliceNest ]
Fast-db	12658 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O15360 [ SRS]    O15360 [ EXPASY ]     O15360 [ INTERPRO ]
Interpro	IPR003516 Fanconia [ SRS ]    IPR003516 Fanconia [ EBI ]
CluSTr	O15360
Pfam	PF03511 Fanconi_A [ SRS ]    PF03511 Fanconi_A [ Sanger ]    pfam03511 [ NCBI-CDD ]
Blocks	O15360
HPRD	06186
	Protein Interaction databases
DIP	O15360
IntAct	O15360
	Polymorphism : SNP, mutations, diseases
OMIM	227650;607139    [ map ]
GENECLINICS	227650;607139
SNP	FANCA [dbSNP-NCBI]
SNP	NM_000135 [SNP-NCI]
SNP	NM_001018112 [SNP-NCI]
SNP	FANCA [GeneSNPs - Utah]  FANCA] [HGBASE - SRS]
HAPMAP	FANCA [HAPMAP]
COSMIC	FANCA [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	FANCA
	General knowledge
Family Browser	FANCA [UCSC Family Browser]
SOURCE	NM_000135
SOURCE	NM_001018112
SMD	Hs.567267
SAGE	Hs.567267
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	DNA repair [Amigo]  DNA repair
GO	protein complex assembly [Amigo]  protein complex assembly
BIOCARTA	Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility    [Genes]
BIOCARTA	BRCA1-dependent Ub-ligase activity    [Genes]
PubGene	FANCA
TreeFam	FANCA
CTD	2175 [Comparative ToxicoGenomics Database]
	Other databases
Other database	Fanconi Anemia Mutation Database
	Probes
Probe	FANCA Related clones (RZPD - Berlin)
	PubMed
PubMed	70 Pubmed reference(s) in LocusLink

Bibliography

Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.

Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H

Nature genetics. 1996 ; 14 (3) : 320-323.

PMID 8896563

Positional cloning of the Fanconi anaemia group A gene. The Fanconi anaemia/breast cancer consortium.

Nature genetics. 1996 ; 14 (3) : 324-328.

PMID 8896564

The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.

Kupfer GM, Nˆ§f D, Suliman A, Pulsipher M, D'Andrea AD

Nature genetics. 1997 ; 17 (4) : 487-490.

PMID 9398857

Sequence variation in the Fanconi anemia gene FAA.

Levran O, Erlich T, Magdalena N, Gregory JJ, Batish SD, Verlander PC, Auerbach AD

Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (24) : 13051-13056.

PMID 9371798

The fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation.

Yamashita T, Kupfer GM, Naf D, Suliman A, Joenje H, Asano S, D'Andrea AD

Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (22) : 13085-13090.

PMID 9789045

Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.

Garcia-Higuera I, Kuang Y, Nˆ§f D, Wasik J, D'Andrea AD

Molecular and cellular biology. 1999 ; 19 (7) : 4866-4873.

PMID 10373536

Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain.

Kruyt FA, Abou-Zahr F, Mok H, Youssoufian H

The Journal of biological chemistry. 1999 ; 274 (48) : 34212-34218.

PMID 10567393

A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation.

Kupfer G, Naf D, Garcia-Higuera I, Wasik J, Cheng A, Yamashita T, Tipping A, Morgan N, Mathew CG, D'Andrea AD

Experimental hematology. 1999 ; 27 (4) : 587-593.

PMID 10210316

Characterization of regions functional in the nuclear localization of the Fanconi anemia group A protein.

Lightfoot J, Alon N, Bosnoyan-Collins L, Buchwald M

Human molecular genetics. 1999 ; 8 (6) : 1007-1015.

PMID 10332032

Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex.

McMahon LW, Walsh CE, Lambert MW

The Journal of biological chemistry. 1999 ; 274 (46) : 32904-32908.

PMID 10551855

High frequency of large intragenic deletions in the Fanconi anemia group A gene.

Morgan NV, Tipping AJ, Joenje H, Mathew CG

American journal of human genetics. 1999 ; 65 (5) : 1330-1341.

PMID 10521298

A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA.

Waisfisz Q, de Winter JP, Kruyt FA, de Groot J, van der Weel L, Dijkmans LM, Zhi Y, Arwert F, Scheper RJ, Youssoufian H, Hoatlin ME, Joenje H

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (18) : 10320-10325.

PMID 10468606

Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.

Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, Ianzano L, Gibson RA, Arwert F, Savoia A, Mathew CG, Pronk JC, Joenje H

Nature genetics. 1999 ; 22 (4) : 379-383.

PMID 10431244

Intracellular localization of the Fanconi anemia complementation group A protein.

Walsh CE, Yountz MR, Simpson DA

Biochemical and biophysical research communications. 1999 ; 259 (3) : 594-599.

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.

Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M, Havenga C, Morgan N, de Winter J, Digweed M, Savoia A, Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E, Mathew CG

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

Human molecular genetics. 2001 ; 10 (23) : 2651-2660.

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.

Yagasaki H, Adachi D, Oda T, Garcia-Higuera I, Tetteh N, D'Andrea AD, Futaki M, Asano S, Yamashita T

Blood. 2001 ; 98 (13) : 3650-3657.

PMID 11739169

Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes.

Yamashita T, Nakahata T

International journal of hematology. 2001 ; 74 (1) : 33-41.

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

Human molecular genetics. 2002 ; 11 (4) : 439-444.

PMID 11854176

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Contributor(s)

Written	04-1998	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated	06-2002	Jean-Loup Huret
		Department of Clinical Genetics and Human Genetics VU University Medical Center Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands
Updated
		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. June 2002 . URL : http://AtlasGeneticsOncology.org/Genes/FA1ID102.html

Huret JL . FANCA (Fanconi anaemia complementation group A). Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/FA1ID102.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:23:30 2008