Revertant mosaicism in fanconi anemia: Natural gene therapy at work

H. Hoehn, R. Kalb, K. Neveling, R. Friedl, A. Bechtold, S. Herterich, Y. Sun, B. Gruhn, H. Hanenberg, D. Schindler

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Scopus citations


One out of four to five patients with Fanconi anemia experience a reversion or attenuation of their constitutional mutations during their lifetime. If the reversion event takes place in a bone marrow stem cell or in an early precursor cell of hematopoiesis, peripheral blood cell counts may gradually recover, leading to improved quality of life. At the beginning of this process, MMC testing will reveal a mixture of MMC sensitive and MMC resistant blood lymphocytes, but after several years MMC sensitive cells (the original FA-cells) may be completely replaced by the progeny of the reverted progenitor cell such that the confirmation of FA requires testing of patient fibroblasts. Molecular analysis reveals the presence of the disease causing biallelic mutations in fibroblast-derived DNA whereas MMC-resistant blood cells show only a single defective allele, explaining their phenotypic reversion. The mechanisms leading to revertant mosaicism include intragenic mitotic recombination (crossing over and gene conversion), back mutation, and compensatory second site mutations. Evidence for each of these mechanisms has been obtained in mosaic FA-patients, but their molecular details are not fully understood. Compound heterozygosity facilitates some of these mechanisms, but reversions have also been observed in homozygous patients. Patients belonging to subtypes FA-A, FA-C, FA-D1, FA-D2 and FA-L have developed revertant mosaicism, with subtypes FA-A and FA-D2 being most frequently involved. Even though the phenomenon of revertant mosaicism has been well documented in FA, there still are many questions: we do not know whether the progeny of a single reverted blood stem or progenitor cell would be able to sustain lifelong hematopoiesis, whether revertant mosaicism provides protection against hematopoietic malignancy, or whether it would be possible to deliberately increase the rate of somatic reversions in order to improve chances for 'natural gene therapy'. Prospective and long-term follow-up studies are needed to answer these questions.

Original languageEnglish (US)
Title of host publicationFanconi Anemia
Subtitle of host publicationA Paradigmatic Disease for the Understanding of Cancer and Aging
EditorsHolger Hoehn, Detlev Schindler
Number of pages24
StatePublished - Dec 1 2007

Publication series

NameMonographs in Human Genetics
ISSN (Print)0077-0876
ISSN (Electronic)1662-3835

ASJC Scopus subject areas

  • Genetics(clinical)

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