Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correctionGross M.a · Hanenberg H.b · Lobitz S.b · Friedl R.a · Herterich S.a · Dietrich R.c · Gruhn B.d · Schindler D.a · Hoehn H.a
aDepartment of Human Genetics, University of Würzburg, Würzburg; bDepartment of Pediatrics, University of Düsseldorf, Düsseldorf; cDeutsche Fanconi Hilfe e.V., Unna-Siddinghausen; dDepartment of Pediatrics, University of Jena, Jena (Germany)
Fanconi anemia (FA) is a genetically and phenotypically heterogenous autosomal recessive disease associated with chromosomal instability and hypersensitivity to DNA crosslinkers. Prognosis is poor due to progressive bone marrow failure and increased risk of neoplasia, but revertant mosaicism may improve survival. Mechanisms of reversion include back mutation, intragenic crossover, gene conversion and compensating deletions/insertions. We describe the types of reversions found in five mosaic FA patients who are compound heterozygotes for single base mutations in FANCA or FANCC. Intragenic crossover could be shown as the mechanism of self-correction in the FANCC patient. Restoration to wildtype via back mutation or gene conversion of either the paternal or maternal allele was observed in the FANCA patients. The sequence environments of these mutations/reversions were indicative of high mutability, and selective advantage of bone marrow precursor cells carrying a completely restored FANCA allele might explain the surprisingly uniform pattern of these reversions. We also describe a first example of in vitro phenotypic reversion via the emergence of a compensating missense mutation 15 amino acids downstream of the constitutional mutation, which explains the reversion to MMC resistance of the respective lymphoblastoid cell line. With one exception, our mosaic patients showed improvement of their hematological status during a three- to six-year observation period, indicating a proliferative advantage of the reverted cell lineages. In patients with Fanconi anemia, genetic instability due to defective caretaker genes sharply increases the risk of neoplasia, but at the same time increases the chance for revertant mosaicism leading to improved bone marrow function.
© 2002 S. Karger AG, Basel
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Biozentrum, University of Würzburg, 97074 Würzburg (Germany)
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M. Gross and H. Hanenberg contributed equally to this work.
Financial support was provided by the “Deutsche Fanconi-Anaemie Hilfe e.V.” and the Schroeder-Kurth Fonds at the University of Wurzburg.
Received 20 November 2002;
manuscript accepted 10 December 2002.
Number of Print Pages : 10
Number of Figures : 6, Number of Tables : 2, Number of References : 41
Cytogenetic and Genome Research
Formerly ‘Cytogenetics and Cell Genetics’
Vol. 98, No. 2-3, Year 2002 (Cover Date: 2002)
Journal Editor: H.P. Klinger, Bronx, N.Y.; M. Schmid, Würzburg
ISSN: 1424–8581 (print), 1424–859X (Online)
For additional information: http://www.karger.com/journals/cgr