RGD Reference Report - Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. - Rat Genome Database

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Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1.

Authors: Navarro, S  Meza, NW  Quintana-Bustamante, O  Casado, JA  Jacome, A  McAllister, K  Puerto, S  Surralles, J  Segovia, JC  Bueren, JA 
Citation: Navarro S, etal., Mol Ther. 2006 Oct;14(4):525-35. Epub 2006 Jul 20.
RGD ID: 11038791
Pubmed: PMID:16859999   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ymthe.2006.05.018   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hematopoietic system disease  ISOBrca2 (Mus musculus)11038791; 11038791 RGD 
hematopoietic system disease  IMP 11038791 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Brca2  (BRCA2, DNA repair associated)

Genes (Mus musculus)
Brca2  (breast cancer 2, early onset)

Genes (Homo sapiens)
BRCA2  (BRCA2 DNA repair associated)


Additional Information