Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism

Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders(1-6), The best know n mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the w ild-type sequence in the other. Here we document for the first time functio nal correction of a pathogenic microdeletion, microinsertion and missense m utation in homozygous Fanconi anaemia(7) (FA) patients resulting from compe nsatory secondary sequence alterations in cis, The frameshift mutation 1615 delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was c ompensated by 3580insCGCTG; and a missense mutation in FANCC (1749T-->G, Le u496Arg) was altered by 1748C-->T, creating a cysteine codon. Although in a ll three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to cross linking agents, thus establishing a functional correction to wild type.