Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA

Fanconi anaemia (FA) is an autosomal recessive disorder characterized by a diversity of clinical symptoms including skeletal abnormalities, progressive bone marrow failure and a marked predisposition to cancer1–4. FA cells exhibit chromosomal instability and hyper-responsiveness to the clastogenic5 and cytotoxic6 effects of bifunctional alkylating (cross-linking) agents, such as diepoxybutane (DEB) and mitomycin C (MMC). Five complementation groups (A–E) have been distinguished on the basis of somatic cell hybridization experiments7–9, with group FA-A accounting for over 65% of the cases analysed10,11. A cDNA for the group C gene (FAC) was reported12 and localized to chromosome 9q22.3 (ref. 8). Genetic map positions were recently reported for two more FA genes, FAA (16q24.3)13 and FAD (3p22–26)14. Here we report the isolation of a cDNA representing the FAA gene, following an expression cloning method similar to the one used to clone the FAC gene12. The 5.5-kb cDNA has an open reading frame of 4,368 nucleotides. In contrast to the 63-kD cytosolic protein encoded by the FAC gene, the predicted FAA protein (Mr 162,752) contains two overlapping bipartite nuclear localization signals and a partial leucine zipper consensus, which are suggestive of a nuclear localization.