• Burtis, Kenneth C, (PI)

Project: Research project


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 date5/1/934/30/98


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


Fanconi Anemia
Clone Cells
Tissue Donors
Polytene Chromosomes
Genome Size
Genetic Therapy


  • Medicine(all)