Genetic basis of Fanconi anemia.

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, a high incidence of myelodysplasia and acute nonlymphocytic leukemia, and cellular hypersensitivity to cross linking agents. Five of the seven known Fanconi anemia proteins bind together in a complex and influence the function of a sixth, FANCD2, which colocalizes with BRCA1 in nuclear foci after genotoxic stress. Carboxy-terminal truncating mutations of the seventh Fanconi anemia gene, BRCA2, are hypomorphic and lead to FA-D1 and possibly FA-B. Because the Fanconi anemia alleles of BRCA2 fail to bind to Rad51 in response to genotoxic stress and Rad51 therefore fails to localize to nuclear damage foci, many investigators in the field suspect that the Fanconi anemia pathway supports the integrity of the Rad51 and BRCA1 and BRCA2 pathways as they function in homologous recombination repair. Because these abnormalities are common to all somatic cells, it is unlikely that dysfunction of this particular pathway results in tissue-specific apoptosis of hematopoietic cells. Indeed, at least one of the Fanconi anemia proteins, FANCC, exhibits functions in hematopoietic cells in addition to its role in the complex. Because FANCC protects hematopoietic cells from apoptotic cues in ways that do not require an intact heteromeric Fanconi anemia complex, it is reasonable to expect that the other Fanconi anemia gene products will have independent cytoplasmic and nuclear functions, particularly in hematopoietic and germ cells that seem to rely so substantially on an intact portfolio of Fanconi anemia proteins.