Fanconi anemia

Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway.

Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and liver tumors.

About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities.

[citation needed] The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pale appearance, feeling tired, and infections.

Because macrocytosis usually precedes a low platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevated red blood cell mean corpuscular volume.

[citation needed] 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.

Observation of monosomy 7 within the marrow is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years (unless prompt allogeneic hematopoietic progenitor cell transplant is an option).

[11] The last major haematological complication associated with FA is bone marrow failure, defined as inadequate blood cell production.

The only treatment left would be a bone marrow transplant; however, such an operation has a relatively low success rate in FA patients when the donor is unrelated (30% 5-year survival).

[citation needed] A recent report by Zhang et al. investigates the mechanism of bone marrow failure in FANCC-/- cells.

Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurred in bone marrow failure.

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.

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.

[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).

[20] In addition, FANCA is required to maintain normal nucleolar morphology, for transcription of pre-rRNA, and global cellular translation.

[42] If no potential donors exist, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to match the recipient's HLA type.

[45] Patients who have had a successful stem cell transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer.

[citation needed] The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells.

A significant number of Fanconi patients have kidney problems, trouble with their eyes, developmental delay, and other serious defects, such as microcephaly (small head).

Recombinational repair of DNA double-strand damage - some key steps. ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks . DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M). [ 13 ] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI. [ 14 ] ATM activates (phosphorylates) CHEK2 and FANCD2 [ 15 ] CHEK2 phosphorylates BRCA1. [ 16 ] Ubiquinated FANCD2 complexes with BRCA1 and RAD51 . [ 17 ] The PALB2 protein acts as a hub, [ 18 ] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B - RAD51C - RAD51D - XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. [ 19 ] RAD51 plays a major role in homologous recombinational repair of DNA during double-strand break repair. In this process, an ATP-dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.