HGNC Approved Gene Symbol: FANCF
Cytogenetic location: 11p14.3 Genomic coordinates (GRCh38): 11:22,622,533-22,625,823 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p14.3 | Fanconi anemia, complementation group F | 603467 | Autosomal recessive | 3 |
By complementation cloning, de Winter et al. (2000) identified the gene mutated in Fanconi anemia group F (603467). They found that the FANCF gene encodes a polypeptide with homology to the prokaryotic RNA-binding protein ROM. The region of homology with ROM comprises the N terminus of the prokaryotic protein, which is the region involved in RNA binding. The homologous region in FANCF is predicted to form an alpha-helical structure. De Winter et al. (2000) suggested that this homology may provide a foothold for functional analysis of the pathway that is defective in FA patients.
De Winter et al. (2000) determined that the FANCF gene has no introns.
De Winter et al. (2000) found that the FANCF cDNA was identical to several ESTs mapped to chromosome 11p15, between microsatellite markers D11S1359 and D11S929.
De Winter et al. (2000) studied the subcellular localizations and mutual interactions of the FA proteins in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA (607139), FANCC (227645), and FANCG (602956). These interactions were detected in wildtype and FANCD (FANCD2; 227646) lymphoblasts, but not in lymphoblasts of other FA complementation groups. The authors hypothesized that each of the FA proteins, except FANCD, is required for complex formation, and that the multiprotein FA complex serves a nuclear function to maintain genomic integrity.
By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al. (2003) identified 3 distinct multiprotein complexes associated with BLM (RECQL3; 604610). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA (607139), FANCG, FANCC, FANCE (600901), and FANCF, as well as topoisomerase III-alpha (TOP3A; 601243) and replication protein A (RPA; see 179835). BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity.
Using yeast 2-hybrid and coimmunoprecipitation assays, Tremblay et al. (2008) found that HES1 (139605), a NOTCH1 (190198) pathway component involved in hematopoietic stem cell (HSC) self-renewal, interacted directly with FANCA, FANCF, FANCG, and FANCL (PHF9; 608111), but not with other FA core complex components. Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to the DNA crosslinking agent mitomycin C (MMC) and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. Tremblay et al. (2008) concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex.
De Winter et al. (2000) identified mutations (613897.0001-613897.0005) in the FANCF gene in 4 cell lines of Fanconi anemia complementation group F.
In 2 patients with a severe phenotype of FANCF, Tryon et al. (2017) identified a c.484_485delCT mutation (613897.0004) in the FANCF gene in compound heterozygosity. Patient 1 additionally carried a 14-bp deletion (c.438_451del; 613897.0006), and patient 2 a 1-bp deletion (613897.0007).
In a 3.5-year-old girl with Fanconi anemia, Zareifar et al. (2019) identified a novel homozygous frameshift mutation (c.534delG; 613897.0008) in the FANCF gene.
Bakker et al. (2012) found that Fancf-knockout mice were born at the expected mendelian distribution and had a normal phenotype at birth. However, Fancf-knockout mice had a reduced overall survival rate and became increasingly tumor prone with age. The types of cancers varied in Fancf-knockout mice, with an excess of lung and ovarian tumors. Fancf-knockout mice had abnormal gonads, similar to other FA mouse models and FA patients. Fancf-knockout ovaries had a strongly reduced primordial follicle pool, implying increased ovarian aging, and some females had an abnormal estrous cycle.
In a cell line (EUFA698) of Fanconi anemia complementation group F (FANCF; 603467), de Winter et al. (2000) found homozygosity for a deletion of nucleotides 230-252 in the FANCF gene.
In the reference Fanconi anemia complementation group F (FA-F) (FANCF; 603467) cell line EUFA121 (Joenje et al., 1997), de Winter et al. (2000) found compound heterozygosity for a 47-bp deletion (349_395del) in the FANCF gene and a 16C-T transition resulting in a gln6-to-ter (Q6X; 613897.0003) nonsense mutation.
For discussion of the gln6-to-ter (Q6X) mutation in the FANCF gene that was found in compound heterozygous state in the reference Fanconi anemia complementation group F (FA-F) (FANCF; 603467) cell line EUFA121 by de Winter et al. (2000), see 613897.0002.
In the Fanconi anemia complementation group F (FA-F) (FANCF; 603467) cell line BD497 in which the FANCF protein was absent, de Winter et al. (2000) found homozygosity for a 2-bp deletion in the FANCF gene (484_485del).
In 2 patients with FANCF with a severe phenotype, Tryon et al. (2017) identified the c.484_485delCT mutation in compound heterozygosity, with a 14-bp deletion (c.438_451del; 613897.0006) in patient 1 and with a 1-bp deletion (c.219delG; 613897.0007) in patient 2. The c.484_485delCT mutation was inherited from the father in both cases. Patient 1 was a 3-year-old girl with multiple congenital anomalies and early-onset bone marrow failure. Patient 2 was a 12-year-old boy with multiple congenital anomalies and early-onset myelodysplastic syndrome. Both patients underwent hematopoietic cell transplant (HCT); patient 1 died 144 days later, and patient 2 was alive at the time of the report approximately 7.5 years after HCT.
In Fanconi anemia complementation group F (FA-F) (FANCF; 603467) cell line EUFA927 in which the FANCF protein was absent, de Winter et al. (2000) found a 327C-G transversion in the FANCF gene resulting in a tyr109-to-ter (Y109X) nonsense mutation.
For discussion of the 14-bp deletion (c.438_451del) in the FANCF gene that was found in compound heterozygous state in patient 1 with Fanconi anemia complementation group F (FANCF; 603467) by Tryon et al. (2017), see 613897.0004.
For discussion of the 1-bp deletion (c.219delG) in the FANCF gene that was found in compound heterozygous state in patient 2 with Fanconi anemia complementation group F (FANCF; 603467) by Tryon et al. (2017), see 613897.0004.
In a 3.5-year-old girl, born of first-cousin Iranian parents, with Fanconi anemia (FANCF; 603467), Zareifar et al. (2019) detected a homozygous 1-bp deletion (c.534delG, NM_022725) in exon 1 of the FANCF gene, resulting in frameshift (G178fs). The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing.
Bakker, S. T., van de Vrugt, H. J., Visser, J. A., Delzenne-Goette, E., van der Wal, A., Berns, A. D., van de Ven, M., Oostra, A. B., de Vries, S., Kramer, P., Arwert, F., van der Valk, M., de Winter, J. P., te Riele, H. Fancf-deficient mice are prone to develop ovarian tumours. J. Path. 226: 28-39, 2012. [PubMed: 21915857] [Full Text: https://doi.org/10.1002/path.2992]
de Winter, J. P., Rooimans, M. A., van der Weel, L., van Berkel, C. G. M., Alon, N., Bosnoyan-Collins, L., de Groot, J., Zhi, Y., Waisfisz, Q., Pronk, J. C., Arwert, F., Mathew, C. G., Scheper, R. J., Hoatlin, M. E., Buchwald, M., Joenje, H. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. (Letter) Nature Genet. 24: 15-16, 2000. [PubMed: 10615118] [Full Text: https://doi.org/10.1038/71626]
de Winter, J. P., van der Weel, L., de Groot, J., Stone, S., Waisfisz, Q., Arwert, F., Scheper, R. J., Kruyt, F. A. E., Hoatlin, M. E., Joenje, H. The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum. Molec. Genet. 9: 2665-2674, 2000. [PubMed: 11063725] [Full Text: https://doi.org/10.1093/hmg/9.18.2665]
Joenje, H., Oostra, A. B., Wijker, M., di Summa, F. M., van Berkel, C. G. M., Rooimans, M. A., Ebell, W., van Weel, M., Pronk, J. C., Buchwald, M., Arwert, F. Evidence for at least eight Fanconi anemia genes. Am. J. Hum. Genet. 61: 940-944, 1997. [PubMed: 9382107] [Full Text: https://doi.org/10.1086/514881]
Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Molec. Cell. Biol. 23: 3417-3426, 2003. [PubMed: 12724401] [Full Text: https://doi.org/10.1128/MCB.23.10.3417-3426.2003]
Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. HES1 is a novel interactor of the Fanconi anemia core complex. Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009. [PubMed: 18550849] [Full Text: https://doi.org/10.1182/blood-2008-04-152710]
Tryon, R., Zierhut, H., MacMillan, M. L., Wagner, J. E. Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations. Am. J. Med. Genet. 173A: 260-263, 2017. [PubMed: 27714961] [Full Text: https://doi.org/10.1002/ajmg.a.37998]
Zareifar, S., Dastsooz, H., Shahriari, M., Faghihi, M. A., Shekarkhar, G., Bordbar, M., Zekavat, O. R., Shakibazad, N. A novel frame-shift deletion in FANCF gene causing autosomal recessive Fanconi anemia: a case report. BMC Med. Genet. 20: 122, 2019. [PubMed: 31288759] [Full Text: https://doi.org/10.1186/s12881-019-0855-2]