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Vol. 98, No. 2-3, 2002
Issue release date: 2002
Section title: Original Article
Cytogenet Genome Res 98:126–135 (2002)
(DOI:10.1159/000069805)

Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction

Gross M. · Hanenberg H. · Lobitz S. · Friedl R. · Herterich S. · Dietrich R. · Gruhn B. · Schindler D. · Hoehn H.
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)

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Article / Publication Details

First-Page Preview
Abstract of Original Article

Received: 11/20/2002
Accepted: 12/10/2002
Published online: 4/14/2003

Number of Print Pages: 10
Number of Figures: 6
Number of Tables: 2

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: http://www.karger.com/CGR

Abstract

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.    


Article / Publication Details

First-Page Preview
Abstract of Original Article

Received: 11/20/2002
Accepted: 12/10/2002
Published online: 4/14/2003

Number of Print Pages: 10
Number of Figures: 6
Number of Tables: 2

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: http://www.karger.com/CGR


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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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