MUTATIONS OF THE FANCONI-ANEMIA GROUP-A GENE (FAA) IN ITALIAN PATIENTS

Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predispositio n to acute myeloid leukemia. At least five complementation groups (FA- A-FA-E) have been identified, The relative prevalence of FA-A has been estimated at an average of similar to 65% but may widely vary accordi ng to ethnic background. In Italy, 11 of 12 patients analyzed by cell- fusion studies were assigned to group FA-A, suggesting an unusually hi gh relative prevalence of this FA subtype in patients of Italian ances try. We have screened the 43 exons of the FAA gene and their flanking intronic sequences in 38 Italian FA patients, using RNA-SSCP. Ten diff erent mutations were detected: three nonsense and one missense substit utions, four putative splice mutations, an insertion, and a duplicatio n. Most of the mutations are expected to cause a premature termination of the FAA protein at various sites throughout the molecule. Four pro tein variants were also found, three of which were polymorphisms. The missense mutation D1359Y, not found in chromosomes from healthy unrela ted individuals, was responsible for a local alteration of hydrophobic ity in the FAA protein, and it was likely to be pathogenic. Thus, the mutations so far encountered in the FAA gene are essentially all diffe rent. Since screening based on the analysis of single exons by genomic DNA amplification apparently detects only a minority of the mutations , methods designed to detect alterations in the genomic structure of t he gene or in the FAA polypeptide may be helpful in the identification of FAA mutations.