Fanconi anemia
Fanconi anemia | |
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autosomal recessive pattern of inheritance. | |
Pronunciation |
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Specialty | Hematology |
Fanconi anemia (FA) is a rare,
FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair via homologous recombination.[1] The well-known cancer susceptibility genes BRCA1 and BRCA2 are also examples of FA genes (FANCS and FANCD1 respectively), and biallelic mutation of any of the two genes usually results in an embryonically lethal outcome, and should the proband come to term, experience a severe form of Fanconi anemia.
Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is
FA occurs in about one per 130,000 live births, with a higher frequency in
Signs and symptoms
FA is characterized by bone marrow failure,
The first sign of a hematologic problem is usually
Genetics
FA is primarily an
Scientists have identified 21 FA or FA-like genes:
The carrier
Because of the failure of hematologic components—
Pathogenesis
Clinically, hematological abnormalities are the most serious symptoms in FA. By the age of 40, 98% of FA patients will have developed some type of
As FA is now known to affect DNA repair, specifically
Myelodysplastic syndromes
MDSs, formerly known as preleukemia, are a group of bone marrow neoplastic diseases that share many of the morphologic features of AML, with some important differences. First, the percentage of undifferentiated progenitor cells,
Acute myeloid leukemia
FA patients are at elevated risk for the development of AML defined as presence of 20% or more of myeloid blasts in the marrow or 5 to 20% myeloid blasts in the blood. All of the subtypes of AML can occur in FA with the exception of promyelocytic. However, myelomonocytic and acute monocytic are the most common subtypes observed. Many MDS patients' diseases evolve into AML if they survive long enough. Furthermore, the risk of developing AML increases with the onset of bone-marrow failure.[citation needed]
Although risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40. Historically, even with a marrow transplant, about a quarter of FA patients diagnosed with MDS/ALS have died from MDS/ALS-related causes within two years,[10] although more recent published evidence suggests that earlier allogeneic hematopoietic progenitor cell transplantation in children with FA is leading to better outcomes over time.[11]
Bone marrow failure
The last major haematological complication associated with FA is bone marrow failure, defined as inadequate blood cell production. Several types of failure are observed in FA patients, and generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible transplant. While most FA patients are initially responsive to androgen therapy and haemopoietic
A recent report by Zhang et al. investigates the mechanism of bone marrow failure in FANCC-/- cells.[12] They hypothesize and successfully demonstrate that continuous cycles of hypoxia-reoxygenation, such as those seen by haemopoietic and progenitor cells as they migrate between hyperoxic blood and hypoxic marrow tissues, leads to premature cellular senescence and therefore inhibition of haemopoietic function. Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurred in bone marrow failure.[citation needed]
Molecular basis
There are 22 genes responsible for FA,[20][21] one of them being the breast-cancer susceptibility gene BRCA2. They are involved in the recognition and repair of damaged DNA; genetic defects leave them unable to repair DNA. The FA core complex of 8 proteins is normally activated when DNA stops replicating because of damage. The core complex adds ubiquitin, a small protein that combines with BRCA2 in another cluster to repair DNA (see Figure Recombinational repair of DNA double-strand damage). At the end of the process, ubiquitin is removed.[2]
Recent 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. According to current models, the complex moves from the cytoplasm into the nucleus following nuclear localization signals on FANCA and FANCE. Assembly is activated by replicative stress, particularly DNA damage caused by cross-linking agents (such as mitomycin C or cisplatin) or reactive oxygen species (ROS) that is detected by the FANCM protein.[22]
Following assembly, the protein core complex activates FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2[23][24][25][26] and FANCI.[27][28]
Monoubiquitinated FANCD2, also known as FANCD2-L, then goes on to interact with a BRCA1/BRCA2 complex (see Figure Recombinational repair of DNA double-strand damage). Details are not known, but similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability.[29][30] With a crippling mutation in any FA protein in the complex, DNA repair is much less effective, as shown by its response to damage caused by cross-linking agents such as cisplatin, diepoxybutane[31] and Mitomycin C. Bone marrow is particularly sensitive to this defect.
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.[citation needed]
FA proteins have cellular roles in autophagy and ribosome biogenesis in addition to DNA repair.[21] FANCC, FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2 are required to clear damaged mitochondria from the cell (a process called mitophagy).[32][33][34][35][36] BRCA1 (also known as FANCS) interacts with the ribosomal DNA (rDNA) promoter and terminator in the nucleolus, the cellular location where ribosome biogenesis initiates, and is required for transcription of rDNA.[37] FANCI functions in the production of the large ribosomal subunit by processing pre-ribosomal RNA (pre-rRNA), the transcription of pre-rRNA by RNAPI, maintaining levels of the mature 28S ribosomal RNA (rRNA), and the global cellular translation of proteins by ribosomes.[20] In the nucleolus, FANCI is predominantly in the deubiquitinated form.[20] In addition, FANCA is required to maintain normal nucleolar morphology, for transcription of pre-rRNA, and global cellular translation.[38] FANCC, FANCD2, FANCG are also required to maintain normal nucleolar morphology and FANCG is also required for global cellular translation.[38] There may be a role for FA proteins outside the nucleolus in ribosome biogenesis or protein translation as FANCI and FANCD2 were the only FA proteins associated with polysomes.[38] Other inherited bone marrow failure syndromes also have defects in ribosome biogenesis or protein translation, including dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman Diamond Syndrome, and like these other diseases, FA may also be a ribosomopathy.[20][21][39]
Spermatogenesis
In humans, infertility is one of the characteristics of individuals with mutational defects in the FANC genes.[40] In mice, spermatogonia, preleptotene spermatocytes, and spermatocytes in the meiotic stages of leptotene, zygotene and early pachytene are enriched for FANC proteins.[40] This finding suggests that recombinational repair processes mediated by the FANC proteins are active during germ cell development, particularly during meiosis, and that defects in this activity can lead to infertility.[citation needed]
Neural stem cell homeostasis
Microphthalmia and microcephaly are frequent congenital defects in FA patients. The loss of FANCA and FANCG in mice causes neural progenitor apoptosis both during early developmental neurogenesis and later during adult neurogenesis. This leads to depletion of the neural stem cell pool with aging.[41] Much of the Fanconi anemia phenotype might be interpreted as a reflection of premature aging of stem cells.[41]
Treatment
The first line of therapy is
Prognosis
Many patients eventually develop
The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. A significant number of Fanconi patients have kidney problems, trouble with their eyes, developmental delay and other serious defects, such as microcephaly (small head).[46]
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- ^ Institut Biologia Fonamental de Barcelona, "Constitutional chromosomal instability: a case with three primary and sequential cancers" Archived 2010-10-03 at the Wayback Machine, USUJ 2009. Retrieved 2010-04-13
- ^ Anemia, Fanconi Archived February 22, 2014, at the Wayback Machine