The emerging genetic and molecular basis of Fanconi anaemia

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Abstract
Fanconi anaemia (FA) is a rare, autosomal, recessive disease that causes life-threatening bone marrow failure, diverse somatic abnormalities and cancer susceptibility. It is characterized by chromosomal instability and hypersensitivity to crosslinking agents, and is genetically heterogeneous. The DNA-damage-response pathway that is altered in FA remains to be elucidated, but the cloning and recent characterization of several FA genes have provided clues as to their function. FA patients are assigned to one of eight FA complementation groups. For six of these, disease genes have been found: FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG. The predicted proteins of these genes lack homologues in non-vertebrates, except for FANCD2. All of them, except for FANCD2, are essential for the assembly of a multiprotein nuclear complex, which is required for FANCD2 to be monoubiquitylated to its active form. Monoubiquitylated FANCD2 co-localizes with BRCA1 to subnuclear foci, the number of which increases upon DNA damage. There is also evidence that the FA pathway has a cytoplasmic component(s). A proportion of FA patients show phenotypic reversion to wild type in lymphocytes. This is due to a correction of the gene defect in haematopoietic stem cells by mitotic recombination, fuelling hopes that gene therapy could be used to treat the life-threatening bone marrow failure that develops in FA patients.