Positional cloning of the Fanconi anaemia group A gene

Abstract

Fanconi anaemia (FA) is an autosomal recessive disorder associated with progressive bone-marrow failure, a variety of congenital abnormalities, and predisposition to acute myeloid leukaemia. Cells from FA patients show increased sensitivity to bifunctional DNA crosslinking agents such as diepoxybutane and mitomycin C, with characteristic chromosome breakage. FA is genetically heterogeneous, at least five different complementation groups (FA-A to FA-E) having been described. The gene for group C (FAC) was cloned by functional complementation and mapped to chromosome 9q22.3 (refs 3, 5), but the genes for the other complementation groups have not yet been identified. The group A gene (FAA) has recently been mapped to chromosome 16q24.3 by linkage analysis, and accounts for 60-65% of FA cases. We narrowed the candidate region by linkage and allelic association analysis, and have isolated a gene that is mutated in FA-A patients. The gene encodes a protein of 1,455 amino acids that has no significant homology to any other known proteins, and may therefore represent a new class of genes associated with the prevention or repair of DNA damage.