Abstract
Somatic mosaicism due to reversion of a pathogenic allele to wild type has been described in several autosomal recessive disorders1,2,3,4,5,6. The best known mechanism involves intragenic mitotic recombination or gene conversion in compound heterozygous patients, whereby one allele serves to restore the wild-type sequence in the other. Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia7 (FA) patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC (1749T→G, Leu496Arg) was altered by 1748C→T, creating a cysteine codon. Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type.
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Acknowledgements
We thank A. Zatterale, A. Georgopoulos and E. Gordon-Smith for referring patients, and Y. Zhi and L. Van Kempen for technical assistance. This work was supported by the Fanconi Anemia Research Fund, the patients support groups from Germany, France, Italy and The Netherlands, Telethon-Italy (E.688), and the European Biomed II program. M.E.H. is supported by a grant from the National Institutes of Health (HL56045) and J.P.d.W. by a grant from the Dutch Cancer Society (VU97-1565).
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Waisfisz, Q., Morgan, N., Savino, M. et al. Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet 22, 379–383 (1999). https://doi.org/10.1038/11956
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DOI: https://doi.org/10.1038/11956
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