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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References
Kvittingen, E.A., Rootwelt, H., Berger, R. & Brandtzaeg, P. Self-induced correction of the genetic defect in tyrosinemia type I. J. Clin. Invest. 94, 1657–1661 (1994).
Ellis, N.A. et al. Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells. Am. J. Hum. Genet. 57, 1019–1027 (1995).
Hirschhorn, et al. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nature Genet. 13, 290–295 (1996).
Stephan, V. et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N. Engl. J. Med. 335, 1563–1567 (1996).
Jonkman, M.F. et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88, 543–551 (1997).
Lo Ten Foe, J.R. et al. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur. J. Hum. Genet. 5, 137–148 (1997).
Auerbach, A.D., Buchwald, M. & Joenje, H. Fanconi anemia. in The Genetic Basis of Human Cancer (eds Vogelstein, B. & Kinzler, K.W.) 317–332 (McGraw-Hill, New York, 1998).
Wijker M. et al. Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene. Eur. J. Hum. Genet. 7, 52–59 (1999).
Savino, M. et al. Mutations of the Fanconi anemia group A gene (FAA) in Italian patients. Am. J. Hum. Genet. 61, 1246–1253 (1997).
Gibson, R.A. et al. Novel mutations and polymorphisms in the Fanconi anemia group C gene. Hum. Mutat. 8, 140–148 (1996).
O'Hara, S.M. & Marnett, L.J. DNA sequence analysis of spontaneous and β-methoxy-acrolein-induced mutations in Salmonella typhimurium hisD3052. Mutat. Res. 247, 45–56 (1991).
von Borstel, R.C. et al. Topical reversion at the HIS1 locus of Saccharomyces cerevisiae. A tale of three mutants. Genetics 148, 1647–1654 (1998).
Ariga, T. et al. A case of Wiskott-Aldrich syndrome with dual mutations in exon 10 of the WASP gene: an additional de novo one-base insertion, which restores frame shift due to an inherent one-base deletion, detected in the major population of the patient's peripheral blood lymphocytes. Blood 92, 699–701 (1998).
DeMarini, D.M., Shelton, M.L., Abu-Shakra, A., Szakmary, A. & Levine, J.G. Spectra of spontaneous frameshift mutations at the hisD3052 allele of Salmonella typhimurium in four DNA repair backgrounds. Genetics 149, 17–36 (1998).
Kwee, M.L. et al. Unusual response to bifunctional alkylating agents in a case of Fanconi anaemia. Hum. Genet. 64, 384–387 (1983).
Joenje, H. et al. Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype. Blood 86, 2156–2160 (1995).
Savoia, A. et al. Fanconi anaemia in Italy: high prevalence of complementation group A in two geographic clusters. Hum. Genet. 97, 599–603 (1996).
Strathdee, C.A., Duncan, A.M. & Buchwald, M. Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nature Genet. 1, 196–198 (1992).
Kruyt, F.A.E., Dijkmans, L.M., Van den Berg, T. & Joenje, H. Fanconi anemia genes act to suppress a cross-linker-inducible p53-independent apoptosis pathway in lymphoblastoid cell lines. Blood 87, 938–949 (1996).
Ishida, R. & Buchwald, M. Susceptibility of Fanconi's anemia lymphoblasts to DNA-crosslinking and alkylating agents. Cancer Res. 42, 4000–4006 (1982).
Kruyt, F.A.E. et al. Cytoplasmic localization of a functionally active Fanconi anemia group A-green fluorescent protein chimera in human 293 cells. Blood 90, 3288–3295 (1997).
Guan, K.L. & Dixon, J.E. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal. Biochem. 192, 262–267 (1991).
Zaman, G.J. et al. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc. Natl Acad. Sci. USA 91, 8822–8826 (1994).
Hoatlin, M.E., Kew, O.M. & Renz, M.E. Regions of poliovirus protein VP1 produced in Escherichia coli induce neutralizing antibodies. J. Virol. 61, 144–1447 (1987).
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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