Reverse mosaicism in Fanconi anemia

Natural gene therapy via molecular self-correction

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

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)126-135
Number of pages10
JournalCytogenetic and Genome Research
Volume98
Issue number2-3
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Fanconi Anemia
Mosaicism
Genetic Therapy
Mutation
Gene Conversion
Bone Marrow
Alleles
Chromosomal Instability
Cell Lineage
Missense Mutation
Heterozygote
Bone Marrow Cells
Neoplasms
Hypersensitivity
Mothers
Observation
Amino Acids
Cell Line
Survival
DNA

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Gross, M., Hanenberg, H., Lobitz, S., Friedl, R., Herterich, S., Dietrich, R., ... Hoehn, H. (2002). Reverse mosaicism in Fanconi anemia: Natural gene therapy via molecular self-correction. Cytogenetic and Genome Research, 98(2-3), 126-135. https://doi.org/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.

In: Cytogenetic and Genome Research, Vol. 98, No. 2-3, 2002, p. 126-135.

Research output: Contribution to journalArticle

Gross, M, Hanenberg, H, Lobitz, S, Friedl, R, Herterich, S, Dietrich, R, Gruhn, B, Schindler, D & Hoehn, H 2002, 'Reverse mosaicism in Fanconi anemia: Natural gene therapy via molecular self-correction', Cytogenetic and Genome Research, vol. 98, no. 2-3, pp. 126-135. https://doi.org/10.1159/000069805
Gross, M. ; Hanenberg, H. ; Lobitz, S. ; Friedl, R. ; Herterich, S. ; Dietrich, R. ; Gruhn, B. ; Schindler, D. ; Hoehn, H. / Reverse mosaicism in Fanconi anemia : Natural gene therapy via molecular self-correction. In: Cytogenetic and Genome Research. 2002 ; Vol. 98, No. 2-3. pp. 126-135.
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