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).

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.

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).