We have investigated the hematopoietic phenotype of mice with a hypomorphic 
mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation). In contrast 
to observations made in other Fanconi anemia (FA) mouse models, low numbers of 
hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) 
mice, either young or adult. Additionally, a high incidence of spontaneous 
chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) 
cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although 
Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a 
very severe hematopoietic syndrome was observed in irradiated 
Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a 
marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells 
(HSCs), compared to wild-type HSCs. Moreover, we have observed for the first 
time in a DNA repair disease model a very significant proliferation defect in 
Brca2(Delta27/Delta27) HSCs maintained in their natural physiological 
environment. The progressive repopulation of wild-type HSCs transplanted into 
unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic 
mosaicism phenomenon observed in a number of genetic diseases, including FA. The 
hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation 
suggests that this FA-D1 mouse model will constitute an important tool for the 
development of new therapies for FA, including gene therapy.