Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction
| Autor: | Helmut Hanenberg, R Dietrich, S. Lobitz, Richard Friedl, Michaela Gross, Detlev Schindler, Holger Hoehn, S. Herterich, B. Gruhn |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Adolescent DNA Mutational Analysis Mutation Missense Biology Compound heterozygosity medicine.disease_cause Fanconi anemia hemic and lymphatic diseases Chromosome instability Genetics medicine Humans Missense mutation Allele Child Molecular Biology Cells Cultured Genetics (clinical) Cell Line Transformed Mutation Base Sequence Mosaicism Cell Cycle Genetic Complementation Test Bone marrow failure Chromosome Breakage medicine.disease FANCA Fanconi Anemia Phenotype Leukocytes Mononuclear |
| Zdroj: | Cytogenetic and Genome Research. 98:126-135 |
| ISSN: | 1424-859X 1424-8581 |
| DOI: | 10.1159/000069805 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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