FANCA (Fanconi anemia, complementation group A)

2012-03-01   Jose Antonio Casado , Juan Antonio Bueren 

Hematopoiesis, Gene Therapy, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas,, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain


Atlas Image
Figure 1. Genomic contex of FANCA gene in chromosome 16. Image adapted from NCBI.



43 exons spanning 80 kb with 4365 bp open reading frame (Lo Ten Foe et al., 1996). The 5-prime region upstream of the putative transcription start site of FANCA has a GC-rich region instead of TATA or CAAT boxes, which is typical of housekeeping genes (Ianzano et al., 1997). Numerous Alu repeats are present in the FANCA gene, suggesting that Alu-mediated recombination may be an important mechanism for the generation of Fanconi anemia-producing mutations.


Multiple transcrips have been described and two types produces proteins; a 5,5 kb mRNA corresponding to NM_000135.2 (5460 bp) and NM_001018112 (1673 bp) by alternative splicing (no experimental confirmation available).


Not described.



Two isoforms with accession number in UniProt; the canonical sequence NP_000126.2 (1455 aa) and NP_001018122.1 (297 aa).


1455 amino acids (163 kDa) conserved in lower vertebrates including zebrafish with 2 nuclear localisation signals (NLS) consensus sequences in N-terminus (Lightfoot et al., 1999), putative peroxidase domain (Ren and Youssoufian, 2001) and a partial leucine zipper in 1069-1090 (Lo Ten Foe et al., 1996), none proven to be functional as such. Despite FANCA protein lack of sequence homologies or motifs that can be assigned to a molecular function, many interactions with other proteins have been described. In this sense, FANCA has a FANCG-binding domain overlapping with NLS region (Waisfisz et al., 1999), a region of interaction with the protein FAAP20 between residues 1095 and 1200 (Ali et al., 2012) or for interaction with BRCA1 through the central part of FANCA protein (aa 740-1083) (Folias et al., 2002).
Through different complexes FANCA can interact with other proteins such as alpha spectrin II, SWI/SNF complex or BLM (DNA-helicase Bloom protein) and other proteins associated with this complex (McMahon et al., 1999; Otsuki et al, 2001; Meetei et al., 2003). FANCA is normally phosphorylated including phosphorylation by ATR-CHK1 on serine 1449 in a process that is required for the formation of the nuclear complex (Collins et al., 2009). FANCA has a consensus sequence for Akt kinase near serine 1149 and its phosphorylation can act as a negative regulator (Otsuki et al., 2002) (Figure 2).
Atlas Image
Figure 2. Scheme of FANCA protein. The sizes of the regions are only approximate.


Wide: brain, liver, placenta, testis, tonsils (mRNA); in mice: protein expression predominant in lymphoid organs, testis, ovary (Van de Vrugt et al., 2000).


FANCA can be cytoplasmic and nuclear where it exerts its primary function.


FANCA is one of the15 known FA proteins that participate in the FA/BRCA pathway which participates in the repair of DNA interstrand cross-links, probably involving homologous recombination and the coordination for other DNA damage repair events, including nucleotide excision repair (NER) and translesion synthesis (Moldovan and DAndrea, 2009). The FA/BRCA pathway may be divided in three parts; 1) FA core complex (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) and six associated factors (FAAP100, FAAP24, FAAP20, HES1, MHF1 and MHF2), 2) ID complex (FANCD2 and FANCI) and 3) downstream FA proteins (FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIP1, FANCP/SLX4, FANCO/RAD51C) (Moldovan and DAndrea, 2009; Ali et al., 2012) (Figure 3).
Several subcomplex are formed in the cytoplasm and from here FANCB-FANCL-FAAP100 are transported together to the nucleus (Ling et al., 2007). FANCA and FANCG form a complex in the cytoplasm, through an N-term FANCA (involving the nuclear localization signal) - FANCG interaction; FANCC join the complex and phosphorylation of FANCA would induce its translocation into the nucleus (Garcia-Higuera et al., 2000; Kruyt et al., 1999). The FA subcomplexes translocates into the nucleus, where FANCE and FANCF are present; and join to the complex (de Winter et al., 2000; kee and DAndrea, 2010). A large FA core complex is generated with FANCM-FAAP24. Interstrand cross-links are recognized by the FANCM-FAAP24-MHF1/2 complex which recruits the rest of the FA core proteins by interaction between FANCM and FANCF. Because of the ubiquitin E3 ligase activity present in FANCL (Hodson et al., 2011) the heterodimer ID complex formed by FANCD2 and FANCI can be monoubiquitinated and then translocated to chromatin, interacting with downstream proteins in the FA pathway such as FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIP1, FANCP/SLX4, FANCO/RAD51C and with BRCA1 (Garcia-Higuera et al., 2001) and the nuclease FAN1 (Liu et al., 2010). These downstream FA proteins are involved in DNA repair by homologous recombination (Moldovan and DAndrea, 2009). In addition to DNA damage, the FA pathway can be activated during S phase of cell cycle. After DNA repair, FANCD2 and FANCI return to the non-ubiquinated form by the action of a complex ubiquitin-specific protease USP1/UAF1 (Nijman et al., 2005) (Figure 3).
Biallelic mutations in FANCA (or in any other gene encoding proteins of the FA core complex) prevent the ubiquitin E3 ligase activity and the monoubiquinitation of FANCD2 and FANCI resulting in a defective FA/BRCA pathway.
Atlas Image
Figure 3. Overview of the FA/BRCA pathway. Fanconi proteins are shown in yellow. Other proteins in the FA core complex necessary for monoubiquitination of the ID complex are shown in blue (FAAP; fanconi anemia associated protein). Downstream proteins involved in the pathway are shown in pink. (ICL: interstrand cross-link). ATR-CHK1 phosphorylates multiple FA and FA-associated proteins including FANCA, FANCE, FANCD2, FANCI and BRCA1. Not all protein interactions are shown and proximity nor imply direct interaction (Adapted from Valeri et al., 2011).


No known complete homology or functional motifs.



Epigenetics: Although hypermethylation of the promotor of different FA genes (FANCD1/BRCA2, FANCB, FANCC, FANCL, FANCN and especially in FANCF) has been described in several sporadic malignancies this effect has not been described so far in FANCA (Valeri et al., 2011).


The number of different pathogenic mutations in FANCA gene is very high. Mutations are heterogeneous; point mutations, splicing mutations, large intragene deletions probably Alu-mediated or insertions have been described (Morgan et al., 1999; Levran et al., 2005). Over 90% of the mutations are private, with about 30% being relatively large deletions. Founder mutations have been described in South Africa and Spanish Gypsies (Tipping et al., 2001; Callen et al., 2005). Unlike mutations in downstream FA genes such as FANCD1/BRCA2 (breast, ovarian, and solid childhood cancer), FANCN/PALB2 (breast cancer) or FANCO/RAD51C (breast and ovarian cancer), FANCJ/BRIP1 (breast cancer and solid childhood cancer), the carriers of monoallelic mutations in FANCA do not seem to have a significant risk of cancer (Garcia and Benitez, 2008). However, It has been recently described in Finnish breast cancer families that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations (Solyom et al., 2011).


In FA-A patients, the presence of wild type cells with a restored FANCA function, can be obtained via back mutation, intragenic crossover, compensating deletions/insertions, or gene conversion of either the paternal or maternal allele. This can lead to a selective advantage of corrected cells generating the so-called somatic mosaicism (Gregory et al., 2001; Gross et al., 2002). The clinical significance of this mosaicism is unclear but there are cases that show improvement of their hematological status when the correction involves hematopoietic stem cells. Somatic mutations and epigenetic silencing in some FA genes occur in a variety of cancers in the general population (non-FA patients) (Valeri et al., 2011). In relation to FANCA, deletions or point mutations were found in several sporadic AML (Tischkowitz et al., 2004; Condie et al., 2002).

Implicated in

Entity name
Fanconi anaemia (FA)
FANCA is implicated in the FA complementation group A (FA-A) that is the most frequent complementation group accounting for about 70% of FA cases, although geographical variations may alter the prevalence in some complementation groups (Casado et al., 2007).
Fanconi anaemia is a chromosome instability syndrome/cancer prone disease (at risk of leukaemia and squamous cell carcinoma), progressive bone marrow failure (pancytopenia), and several congenital abnormalities mainly: skin hiperpigmentation, skeletal malformation, small stature or urogenital abnormalities (Auerbach, 2009).
Fanconi anaemias prognosis is poor; mean survival is 20 years: patients die of bone marrow failure (infections, haemorrhages), leukaemia, or solid cancer specially squamous carcinomas (SCC) in adult patients. Hematopoietic stem cell transplantation with a suitable HLA-matched donor is currently the best treatment to cure the aplastic anemia or leukaemia (Gluckman and Wagner, 2008).
It has 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 (Faivre et al., 2000). However, in another recent study, no clinical differences in terms of onset of hematologic disease and number of congenital anomalies were found in patients with expression of a mutant form of FANCA protein compared with patients without expression of the protein (Castella et al., 2011).
Compared to control cells, an increase of chromatid-type aberrations (breaks, gaps, interchanges; increased rate of breaks) is observed in FA cells when samples are treated with specific clastogens known as DNA inter-strand cross-linking agents (e.g. mitomycin C, diepoxybutane). Theses agents are widely used for FA diagnosis (Auerbach, 1993).


Pubmed IDLast YearTitleAuthors
223439152012FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway.Ali AM et al
171057502007A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network.Antonio Casado J et al
196224032009Fanconi anemia and its diagnosis.Auerbach AD et al
155229562005A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain.Callén E et al
212733042011Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.Castella M et al
191095552009ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function.Collins NB et al
126858432002Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.Condie A et al
111106742000Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.Faivre L et al
123547842002BRCA1 interacts directly with the Fanconi anemia protein FANCA.Folias A et al
182585062008The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets.García MJ et al
112394542001Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.Garcia-Higuera I et al
180843322008Hematopoietic stem cell transplantation in childhood inherited bone marrow failure syndrome.Gluckman E et al
112262732001Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells.Gregory JJ Jr et al
116734082001Fanconi anemia and DNA repair.Grompe M et al
126979942002Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.Gross M et al
217754302011Structural analysis of human FANCL, the E3 ligase in the Fanconi anemia pathway.Hodson C et al
91691261997The genomic organization of the Fanconi anemia group A (FAA) gene.Ianzano L et al
207135142010Expanded roles of the Fanconi anemia pathway in preserving genomic stability.Kee Y et al
105673931999Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain.Kruyt FA et al
156436092005Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.Levran O et al
103320321999Characterization of regions functional in the nuclear localization of the Fanconi anemia group A protein.Lightfoot J et al
173961472007FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.Ling C et al
206711562010FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.Liu T et al
88965631996Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.Lo Ten Foe JR et al
105518551999Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex.McMahon LW et al
127244012003A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.Meetei AR et al
196860802009How the fanconi anemia pathway guards the genome.Moldovan GL et al
105212981999High frequency of large intragenic deletions in the Fanconi anemia group A gene.Morgan NV et al
156943352005The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway.Nijman SM et al
117265522001Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.Otsuki T et al
118558362002Phosphorylation of Fanconi anemia protein, FANCA, is regulated by Akt kinase.Otsuki T et al
111618292001Functional analysis of the putative peroxidase domain of FANCA, the Fanconi anemia complementation group A protein.Ren J et al
212365612011Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family.Solyom S et al
113443082001Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.Tipping AJ et al
147497032004Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia.Tischkowitz MD et al
214931812011Fanconi anaemia: from a monogenic disease to sporadic cancer.Valeri A et al
104686061999A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA.Waisfisz Q et al
110637252000The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and Winter JP et al
107541102000Cloning and characterization of murine fanconi anemia group A gene: Fanca protein is expressed in lymphoid tissues, testis, and ovary.van de Vrugt HJ et al

Other Information

Locus ID:

NCBI: 2175
MIM: 607139
HGNC: 3582
Ensembl: ENSG00000187741


dbSNP: 2175
ClinVar: 2175
TCGA: ENSG00000187741


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
FA core complexKEGGhsa_M00413
FA core complexKEGGM00413
Fanconi Anemia PathwayREACTOMER-HSA-6783310


Pubmed IDYearTitleCitations
265840492015The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
191095552009ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function.43
190124932009Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer.41
190156342009Fanconi anemia deficiency stimulates HPV-associated hyperplastic growth in organotypic epithelial raft culture.35
212733042011Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.33
186766802008Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.32
151382652004Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins.27
124440972002Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants.25
180561552008Comprehensive association testing of common genetic variation in DNA repair pathway genes in relationship with breast cancer risk in multiple populations.25


Jose Antonio Casado ; Juan Antonio Bueren

FANCA (Fanconi anemia, complementation group A)

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version:

Historical Card

2002-06-01 FANCA (Fanconi anemia, complementation group A) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

2001-12-01 FANCA (Fanconi anemia, complementation group A) by  Hans Joenje 

Department of Clinical Genetics, Human Genetics VU University Medical Center Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands

1998-04-01 FANCA (Fanconi anemia, complementation group A) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France