Disease relevance of Fanconi Anemia

• Phenotypic correction of Fanconi anemia in human hematopoietic cells with a recombinant adeno-associated virus vector [1].
• The 10 cell lines represented five genetic disorders: Bloom syndrome, familial polyposis, Fanconi anemia, Gardner syndrome, and xeroderma pigmentosum, complementation groups A(XP-A), C(XP-C), E(XP-E), and variant (XP-Va) [2].
• Cultured cells from individuals affected with Fanconi anemia (FA) exhibit spontaneous chromosome breakage and hypersensitivity to the cell killing and clastogenic effects of the difunctional alkylating agent diepoxybutane (DEB) [3].
• These disorders include ataxia telangiectasia, Bloom's syndrome, Fanconi anemia, xeroderma pigmentosum, and Nijmegen breakage syndrome, all of which are very rare and are inherited in a recessive manner [4].
• The diagnosis of Fanconi anemia (FA) is based on the association of congenital malformations, bone marrow failure syndrome, and hypersensitivity to chromosomal breaks induced by cross-linking agents [5].

High impact information on Fanconi Anemia

• The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair [6].
• Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage-response pathway [7].
• Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage-response network involving BRCA1 and BRCA2 (refs. 2,3) [7].
• The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia [8].
• We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia-associated proteins [7].

Chemical compound and disease context of Fanconi Anemia

• Eight patients with Fanconi's anemia were given cyclophosphamide alone (seven patients) or combined with procarbazine and antithymocyte globulin (one patient) followed by marrow grafts from HLA-identical siblings [9].
• A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA [10].
• In multivariable, stepwise proportional hazards models, azathioprine therapy (P < .0001) and the diagnosis of Fanconi anemia (P < .0001) were significant factors for all patients [11].
• A damage-recognition protein which binds to DNA containing interstrand cross-links is absent or defective in Fanconi anemia, complementation group A, cells [12].
• Cells derived from Fanconi anemia (FA) patients are hypersensitive for cross-linking agents, such as cisplatin, that are potent inducers of programmed cell death (PCD) [13].

Biological context of Fanconi Anemia

• Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knock-down of BRIP1 leads to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia [6].
• Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA [7].
• Here we show that the protein defective in individuals with Fanconi anemia belonging to complementation group B is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA [14].
• Monoubiquitination of the FANCD2 protein is a key step in the Fanconi anemia (FA) tumor suppressor pathway, coinciding with this molecule's accumulation at sites of genome damage [15].
• The fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation [16].

Anatomical context of Fanconi Anemia

• Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L) [17].
• Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling [18].
• Bone marrow failure is a consistent feature of Fanconi anemia (FA) but it is not known whether the bone marrow failure is a direct and specific result of the inherited mutation or a consequence of accumulated stem cell losses resulting from nonspecific DNA damage [19].
• Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells [19].
• We have studied the pattern of chromosome instability in cultured fibroblasts and fetal membrane cells from a fetus aborted by an individual with a history of a previous child affected with Fanconi anemia (FA) [20].

Gene context of Fanconi Anemia

• Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways [21].
• We found that spontaneous SCE levels were elevated approximately 2-fold in chicken DT40 cells deficient in Fanconi anemia (FA) gene FANCC [22].
• A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA [23].
• BRCA1 interacts directly with the Fanconi anemia protein FANCA [24].
• The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC [25].

Analytical, diagnostic and therapeutic context of Fanconi Anemia

• Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis [26].
• A simplified approach to improve the efficiency and safety of ex vivo hematopoietic gene therapy in fanconi anemia patients [27].
• Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice [28].
• OBJECTIVE: The aim of this study was to develop a rapid laboratory procedure that is capable of subtyping Fanconi anemia (FA) complementation groups FA-A, FA-C, FA-G, and FA-nonACG patients from a small amount of peripheral blood [29].
• Moreover, the mus308 mutation has been proposed as an animal model for the study of Fanconi's anemia [30].

References