Fanconi Anemia

Author: Alberto Inghirami
Date: 14/01/2015



Fanconi Anemia is a congenital disease caused by a mutation that affects the Fanconi Anemia Complementation Group.

The Disease DatabaseFanconi Anemia
WikipediaFanconi Anemia
MedlinePlusFanconi Anemia


On average it affects 1 in 350000 childbirths. This disease is more present in Ashkenazi Jews and Afrikaners in South Africa.


Generally the signs/symptoms are noted in early childhood, and they include:

1. Short stature
2. Skeletal anomalies
3. Pigmentation anomalies, including Café au Lait spots
4. Abnormal kidney formation
5. Abnormal heart, lungs and Digestive tract
6. Bone Marrow Failure
The Signs/Symptoms that are given by Bone Marrow Failure include:
• Fatigue
• Pallor
• Petechiae
• Bruising
• Frequent Infections
• Macrocytic Anemia
• Thrombocytopenia


If the suspected patient manifests the typical signs/symptoms of this disease, and there is a hereditary pattern of these symptoms in the patients family (Pedigree Analysis), the physician can request further genetic evaluation by a specialist (Laboratory Tests) to confirm the diagnosis. These include:

A) Chromosome breakage test: An exam that test the fragility of one's Chromosomes.

B) Cytometric Flow Analysis: An exam that test chromosome durability when exposed to certain chemical substances

C) Mutation Screening: Look for the mutations of interest that the patient may carry.

How is Fanconi Anemia Diagnosed?, NIH


90% of patients with Fanconi Anemia develop Bone Marrow Failure by the age of 40. The majority of individuals that suffer from Fanconi Anemia (FA) have an endocrine pathology as well. Because this is an autosomic recessive genetic disorder, one must be homozygous for the mutated gene to manifest the disease. There have been identified 17 different genes that can be mutated in patients with FA. These genes include FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCP, FANCS, RAD51C, and XPF. The mutation of the FANCB gene is present on the X chromosome, therefore it is the only exception to the autosomic recessive transmission of the disease.

Fanconi's Anemia Orphanet Encyclopedia, October 2003

The FA complementation group is a protein family that has an important role in interstrand DNA cross-link repair as well as chromosome stability. The members that form a common protein complex (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL) can directly bind to damaged DNA strands in the nucleus along with the BRCA1 protein. The actual DNA repair is carried out by the ID complex, which is made up by the interaction of FANCD2 and FANCI. These two subunits are activated via monoubuquitination and phosphorylation. The ID complex can bind directly to chromatin where the damage is present and work with other DNA repair proteins like BRCA1 and BRCA2. Patients that suffer from FA have mutations that impair the correct functioning of this protein complex; therefore they lack the activation of the FANC-BRCA1/BRCA2 DNA repair mechanism.

Expanded roles of the Fanconi anemia pathway in preserving genomic stability, 2010

FANCA has a subunit that allows the FANC complex to assemble on both single strand damaged DNA as well as double strand damaged DNA. FANCA then can interact and anchor the FA core complex, formed by the other members of the FA complementation group. At this point FANCD2 and FANCI can be mono-ubuiquitinated and thus the ID complex is activated to repair the DNA. There is also evidence that FANCM has a direct role in DNA repair as well. Any mutation that interferes with the correct functioning of this protein complex, especially with the monoubuquitination of the ID complex, results in a reduction of the cell's DNA repair capabilities.

These proteins have an important role in the maintenance and repair of DNA damage due to reactive oxygen species (ROS). One of the main proteins to consider is the FANCC, for it has a crucial role in oxidative stress signaling in several cell types. It has been proven that FANCC (located on chromosome 9q22.3) interacts with Nicotinamide Adenine Dinucleotide Phosphate (NADPH) and cytochrome P450 reductase and gluthathione S-transferaseP1-1. All of these components are involved in the detoxification of reactive oxygen species or reactive intermediates.

A major switch for the Fanconi anemia DNA damage–response pathway, 2008

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

UCSC Genome Browser

Wikipedia ROS


Because FA is an Autosomal Recessive disorder, in most cases, this means that one must inherit both mutated genes from their parents in order to manifest the disease. Most of the mutations are found on the non-sex chromosomes (except for FANCB, which is found on the X chromosome).
What is the risk of inheriting this disease?

If one has two Heterozygous parents then the probabilities are:
25%: Born with two normal genes
50%: Heterozygous carrier of the mutated gene
25%: Homozygous for the mutated gene and thus affected by FA

If the mutated gene (FANCB) is found on the X chromosome, then males of parents carrying the mutation are at a higher risk of inheriting the disease.

Autosomal Recessive, MedlinePlus


Effects of Oxygen saturation variation in the bone marrow on FANCC-/- erythroid precursor cells.

It has been noted that there are different oxygen gradients in bone marrow tissue. The differences in oxygen concentration play an important role in the maintenance of the stem cell population as well as the development of the progenitor cell population. It can be deduced that the cells that migrate from the more hypoxic areas of the bone marrow tissue into a more oxygenated area will suffer greater oxidative damage, “reoxygenated oxidative stress.” DNA damage induced by ROS activates p53, which in turn can mediate cell cycle arrest or apoptosis if the damage is beyond repair.

Cell Biology WIKI

Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia, 2007

The proteins of the FA family have an important role in DNA damage repair of both single and double strand breaks. It was found that cells with a non-functional FA protein complex, due to mutations of one of the elements in the complex, made the stem cells more sensitive to DNA damage thanks to the transition from a hypoxic to a normoxic environment.

In the bone marrow the oxygen tension varies approximately from 5-6% to normoxia. Experimental evidence shows that Hemopoietic Stem Cells are mostly found in the hypoxic areas of the bone marrow tissue. This data indicates that hypoxia has an important role in normal hemopoiesis. As a result the cells that are part of the hemopoietic process are exposed to different oxygen gradients, low to high, making them susceptible to oxidative damage. This would imply that these hemopoietic cells need a valid DNA damage repair mechanism to counteract the oxidative damage, which is missing in patients with Fanconi anemia.

Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia, 2007

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

An experiment, carried out by Zhang et al., recreated the oxygen gradient variations on hemopoetic cells with FANC-/- (a member for the protein complex) mutations to see how they would react to the oxygen variation, even though they lack an important DNA repair mechanism. As a result the cells that carried the homozygous mutation showed a reduced number of BFU-E and CFU-GM colonies, a slight increase in apoptosis, and an increase in senescence as apposed to the control colonies.

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

Reduction of BFU-E and CFU-GM colonies:
The scientists exposed the wild type and the cells carrying the FANCC mutation to an environment that was first hyperoxic (21%) then hypoxic (1%), followed by another hyperoxic exposure at 21%. As a control, both the WT and the FANCC-/- cells where left in a hypoxic environment alone (Con groups). Results show (bar graph E in figure below) that both the WT and mutated cells suffer a reduction in the number of CFU-GM and BFU-E colonies when reoxygenated, but the cells carrying the FANCC mutation suffered a significant reduction. We can deduce at this point that the transition between different oxygen concentrations has a greater inhibitory effect on FANCC-/- bone marrow progenitor cells.

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

Slight increase in apoptosis reoxygenation:
The amount of apoptosis was monitored in two different time frames, one immediately after the reoxygentation treatment (8 and 16 hours), and after a two-week culture of the progenitor cells. Results show that there was in increase in apoptosis in both WT and FANCC-/- cells in the 8 hours following the reoxygenation period. Yet after 16 hours the amount of apoptotic cells decreases in both the wt and FANCC-/- cells (figure d above). Looking at the amounts of apoptosis (caspase 3 activity, figure c below) after a two week culture one can see that there is a modest increase in the amount of apoptotic cells in both groups.

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

A biomarker for senescence, SA-Beta-gal, was used to investigate if the FANCC-/- cells underwent senescence after reoxygentation treatment. This study was carried out after two weeks from when the treatment was completed. The results show that there was an increase in the staining of the cells for SA-Beta-gal (figure a below). Then a quantitative analysis of the cells was carried out in relation to the phase of the cell cycle with which they where found. The majority, approximately 70.6%, of the FANCC-/- cells were in the G0 and G1 phase of the cell cycle. One can deduce that DNA damage did occur as a result of reoxygination, however this damage in most cases was not enough to induce apoptosis. As a result most of the cells remain in a senescent state.

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

Molecular mechanisms:

Another point that was investigated was the expression of proteins that are involved in cell senescence, like p53, p21, p19 etc. It was found that more than 50% of FANCC-/- cells where positive for p53 at two weeks from the reoxygentation treatment, which was greater than the untreated FANCC-/- cells and the WT treated cells. No p53 expression was detected in the untreated WT cells. There was also a greater amount of p21 expression in FANCC-/- cells that were treated with the reoxygentation cycle. Western blot analysis confirmed this data. It was also noted that there was also an accumulation of p16 in FANCC-/- cells, even though to a lesser extent. It is known that p53 can block the cell cycle by direct interaction with the cells DNA inducing the expression of other cell cycle regulators like p21 and various miRNA. P21 and p16 interact and inhibit Cyclin-dependent kinases, which are vital for the progression of the cell cycle. As a result of the accumulation of proteins like p53, p21, and p16, there is a block on the progression of the cells from the G1 phase to the S phase of the cell cycle.

The Battle between Tumor Suppressors: Is Gene Therapy Using p16INK4a More Efficacious Than p53 for Treatment of Ovarian Carcinoma?, 2001

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005


Patients that have FA suffer a variety of different signs and symptoms linked to the dysfunction of the FANC protein complex which can be life threatening. One of the main effects of the disease is macrocytic anemia. What the studies that have been carried out up until know show is that the HSC carrying a dysfunctional FA protein complex cannot correctly produce red blood cells in the physiological bone marrow’s oxygen gradient. The difference of oxygen levels within the bone marrow tissue is to “stressful” of an environment for the HSC of FA patients to produce normal red blood cells. The studies carried out by Zhang et al show that indeed the oxidative stress is the culprit for the inhibitory effects of the hyperoxic-hypoxic-hyperoxic treatments. It was shown that the negative effects of the reoxygentation treatment where abrogated on the FANC-/- cells when a ROS scavenger (NAC) was added to the cells growth terrain. One can deduce at this point that FANC-/- HSC cells are indeed hypersensitive to oxidative damage. What is interesting is that HSC do not all go into apoptosis but rather tend to remain senescent in G0 or G1. As a result these patients suffer anemia because of cellular senescence. Therefore this could be a component of the etiology of the anemia in patients carrying a non-functional FA protein complex. Further investigation could clarify the molecular mechanisms of this disease and their role in the development of a mieloproliferative disorders.

Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cell, 2005

The main complications that a patient can develop are myeloproliferative disorders like leukemia, and/or a myelodisplastic disorders. There is also a high risk of one developing cancer of the head, neck, and urinary tract. Other disorders are linked to the malformation of the kidneys, microcephaly, ocular defects as well as the failure to thrive. As a result of the various complications associated with this disease, most patients do not reach adulthood.

MedlinePlus Fanconi Anemia


The outlook for this disease is not very promising, but thanks to new treatments, including bone marrow transplants, we can prolong the life spans of patients suffering from this anemia. What are other possible future therapeutic solutions to take into consideration? If one could atleast limit the damage caused by the ROS, it could improve the prognosis. The idea would be to improve the prognosis by treating the oxidative damage. This therapeutic strategy could prove itself to be quick and cost effective. There is obviously still a lot of research to do on the subject, but by getting a better understanding of the disease, one could develop a better treatment to improve the quality of life of these patients.

MedlinePlus Fanconi Anemia

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