Abstract
Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two sub-populations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to >100 nM compared to a mean of 2 ± 2 nM for 20 nonmosaic FA patients and 49 ±11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9–30 years.
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Acknowledgements
We thank Franca di Summa and Carola van Berkel for expert technical assistance, Prof. Dr. Leo P. ten Kate for valuable comments on the manuscript, and Dr. Vicky A. Athens for her cooperation in this study. This work was supported by the European Cancer Centre Amsterdam (ECC), EUFAR (a concerted action sponsored by the European Union, contract PL931562), the FA Research Fund, Inc., Eugene, Oreg., The Medical Research Council (UK), and the patient support organizations in Italy, France, Germany and The Netherlands.
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Ten Foe, J.R.L., Kwee, M.L., Rooimans, M.A. et al. Somatic Mosaicism in Fanconi Anemia: Molecular Basis and Clinical Significance. Eur J Hum Genet 5, 137–148 (1997). https://doi.org/10.1007/BF03405891
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DOI: https://doi.org/10.1007/BF03405891
