(Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Barcelona, Spain)

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure and cancer predisposition. In order to investigate the origin, functional role and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not due to a mutational "hot-spot", but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause FA by originating large interstitial deletions involving FANCA and two adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematological disease or number of malformations.