Fanconi anemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]


In order to understand the pathophysiology, it is important to understand normal physiology of DNA repair. There are eight FANC family members that are activated during times of DNA damage. These proteins function in repairing damaged genetic material. In patients with Fanconi anemia, there is impaired DNA damage response due to mutations in the FANC family genes, and this leads to chromosomal instability and susceptibility to cross-linking agents. These cross-linking agents can lead to the generation of reactive oxygen species.


Normal physiology

  • The FANC complex: Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 1990s, little information was known about the proteins encoded by FA genes. However, more recently, studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M assemble to form a core protein complex in the nucleus. This complex has also been suggested to exist in cytoplasm and its translocation into the nucleus is dependent on the nuclear localization signals on FANCA and FANCE. Assembly is thought to be activated by DNA damage due to cross-linking agents or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage. Following assembly, the protein core complex activates FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2. It was previously thought that BRCA1, with its zinc finger ubiquitin ligase domain was responsible for the post-transcriptional modification of FANCD2. However, this has since been invalidated and BRCA1 interaction with the FA protein complex is still being investigated. Ubiquinated FANCD2, also know as FANCD2-L, then goes on to interact with a BRCA1/BRCA2 complex. Again, details of this interaction have yet to be discovered. However, it is already known that similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability. With a crippling mutation in any FA protein in the complex, DNA repair has been shown to be much less effective, as can be seen from the damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C.
  • Other FA protein interactions: Although the above described pathway seems to be the most integral part of the DNA damage response in cells and explains the pathology of FA, novel approaches have determined that most FA proteins have an alternate role. Recent investigations on FANCC, one of the intensively studied proteins, have shown that it plays an important role in cellular responses to oxidative stress. For example, it has been found to interact with NADPH cytochrome P450 reductase, associated with increased production of ROS, and glutathione S-transferase, responsible for production of the anti-oxidant glutathione. These two enzymes are both involved in either triggering or detoxifying ROS. Not surprisingly, mice with Cu/Zn superoxide dismutase and FANCC mutations demonstrate defective haemopoiesis. FANCC was also shown to bind STAT1 and help receptor docking and phosphorylation of STAT135, which helps in tumor suppression. This leads to the conclusion that FANCC participates in cell growth arrest and cell cycle progression, inhibiting apoptosis, a possible cause of bone marrow failure due to depletion of haemopoietic progenitors. Another FA protein linked to protection against oxidative damage is FANCG. This protein interacts with cytochrome P450 2E1 suggesting a possible role in detoxifying cytochrome ROS, produced readily by the members of this superfamily36. Furthermore, FANCG is identical to post-replication repair protein XRCC9, hinting at the possibility that FANCG also interacts directly with DNA by means of its internal leucine zipper. Thus it is readily seen that FA proteins also acts outside of the Fanconi pathway, either by helping neutralize ROS or by taking part in DNA repair. Such mechanisms help understand the causes behind bone marrow failure, where reoxygenation-induced oxidative stress is very common. Furthermore, it is known that cross-linking agents produce ROS and it is possible that FA cell hypersensitivity to cross-linkers is not due directly to them, but rather to the cell’s impaired ability to cope with increased ROS production.

Abnormalities in Fanconi anemia

The pathophysiology of Fanconi anemia largely stems from mutations that predispose cells to impaired DNA damage response, leading to bone marrow failure and increasing the risk for various cancers.[1][2][3][4][5][6][7][8][9] In tissues and bone marrow, in which successful cell replication is vital, there can be increased susceptibility to DNA-damaging agents. Cellular function will be severely affected by FA protein dysfunction where FA leads to decreased hematopoiesis and bone marrow failure due to progenitor and stem cell senescence. In another pathway responding to ionizing radiation, FANCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks, and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistant DNA synthesis, the hallmark of a defect in the S phase checkpoint, in patients with FA-D1 or FA-D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of AML in these patients.


  1. Guan J, Fransson S, Siaw JTT, Treis D, Van den Eynden J, Chand D; et al. (2018). "Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib". Cold Spring Harb Mol Case Stud. doi:10.1101/mcs.a002550. PMID 29907598.
  2. Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O; et al. (2018). "From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia". Genet Med. doi:10.1038/s41436-018-0037-1. PMID 29904161.
  3. Kulanuwat S, Jungtrakoon P, Tangjittipokin W, Yenchitsomanus PT, Plengvidhya N (2018). "Fanconi anemia complementation group C protection against oxidative stress‑induced β‑cell apoptosis". Mol Med Rep. doi:10.3892/mmr.2018.9163. PMID 29901137.
  4. Yin H, Ma H, Hussain S, Zhang H, Xie X, Jiang L; et al. (2018). "A homozygous FANCM frameshift pathogenic variant causes male infertility". Genet Med. doi:10.1038/s41436-018-0015-7. PMID 29895858.
  5. Maung KZY, Leo PJ, Bassal M, Casolari DA, Gray JX, Bray SC; et al. (2018). "Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia". Blood Cancer J. 8 (6): 50. doi:10.1038/s41408-018-0090-7. PMC 6002376. PMID 29891941.
  6. Velimezi G, Robinson-Garcia L, Muñoz-Martínez F, Wiegant WW, Ferreira da Silva J, Owusu M; et al. (2018). "Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48". Nat Commun. 9 (1): 2280. doi:10.1038/s41467-018-04649-z. PMC 5996029. PMID 29891926.
  7. Castilla-Cortazar I, Aguirre GA, De Ita JR (2018). "About a Suggestive Association Between Fanconi Anemia and Laron Syndrome". Am J Med Sci. 355 (6): 615–616. doi:10.1016/j.amjms.2018.02.004. PMID 29891047.
  8. García-de Teresa B, Frias S (2018). "In Reference to Fanconi Anemia and Laron Syndrome". Am J Med Sci. 355 (6): 614–615. doi:10.1016/j.amjms.2018.01.014. PMID 29891046.
  9. Douiev L, Saada A (2018). "The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage". Biochim Biophys Acta. doi:10.1016/j.bbabio.2018.06.004. PMID 29886046.