• Burtis, Kenneth C (PI)

Project: Research project

Project Details


The primary goal of this proposal is to clone the Fanconi anemia A (FA-A) gene of man through an analysis of the functionally homologous mus3O8 gene of Drosophila. This hematological disorder is a candidate for human gene therapy. Current support for gene homology between these two organisms is provided by the observation that among several mutagen sensitive disorders in man only Fanconi anemia is characterized by hypersensitivity to DNA cross-linking agents and concurrent insensitivity to monofunctional alkylating agents. An extensive search for analogous mutants in Drosophila has revealed only one autosomal gene with this property; the mus3O8 gene. The presence of this unique spectrum of mutagen sensitivity in mutants of only one disorder in man and one in Drosophila strongly suggests that the mus3O8 gene encodes a function analogous to one of the Fanconi genes. That suggestion is further supported by the demonstration that both Fanconi anemia cells and mus308 cells exhibit an elevated frequency of spontaneous chromosomal aberrations. Two additional rare phenotypes are common to both the mus3O8 mutants and cells deficient in the FA-A gene. These are a failure to recover DNA synthesis following mutagen treatment and the unique alteration of a deoxyribonuclease. Because the mus3O8 mutants and FA-A cells share a total of four rare properties, there is therefore a strong probability that they are functionally related. This potential functional homology has stimulated efforts to clone the Drosophila mus3O8 gene in preparation for cloning the human analogue. The feasibility of that approach is supported by numerous examples in which cloned genes from one of these organisms has been employed to recover the homologous gene from the alternate organism. Recovery of the FA-A gene can be definitively verified by testing the capacity of the cloned gene to complement the hypersensitivity of FA-A cells to DNA crosslinking agents following transfection. This approach has been chosen because all of the direct mammalian efforts, including an approach recently employed to clone the FA C gene, have thus far failed to recover the FA-A gene. Drosophila was chosen for this study because gene cloning in this organism is facilitated by genetic analysis, the presence of giant polytene chromosomes and a small genome size. It is anticipated that recovery of the human gene will place our collaborators in a position to determine if it can be employed to reverse the lethal effects of Fanconi anemia through gene therapy. This approach is particularly pertinent to Fanconi anemia because the most frequent cause of lethality in this disease is a failure of bone marrow cells to proliferate in late adolescence. This disorder can be reversed in Fanconi children, however, by bone marrow transplantation when a compatible donor is available. If, however, the patients own stem cells could be provided with the normal gene, then each individual could serve as his or her own donor.
Effective start/end date5/1/938/31/01


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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