Germ cell defects and hematopoietic hypersensitivity to γ-interferon in mice with a targeted disruption of the Fanconi anemia C gene

Fanconi anemia (FA) is an autosomal recessive chromosome instability syndrome characterized by progressive bone marrow (BM) failure, skeletal defects, and increased susceptibility to malignancy. FA cells are hypersensitive to DNA cross-linking agents, oxygen and have cell cycle abnormalities. To dev...

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Bibliographic Details
Published in:Blood 1996-07, Vol.88 (1), p.49-58
Main Authors: WHITNEY, M. A, ROYLE, G, BAGBY, G. C, GROMPE, M, LOW, M. J, KELLY, M. A, AXTHELM, M. K, REIFSTECK, C, OLSON, S, BRAUN, R. E, HEINRICH, M. C, RATHBUN, R. K
Format: Article
Language:English
Subjects:
Anemias. Hemoglobinopathies
Animals
Base Sequence
Biological and medical sciences
Cell Cycle
Cell Cycle Proteins
Cells, Cultured
Chemokine CCL4
Chromosome Aberrations
Colony-Forming Units Assay
Cross-Linking Reagents - pharmacology
Diseases of red blood cells
DNA Damage
DNA-Binding Proteins
Exons - genetics
Fanconi Anemia - genetics
Fanconi Anemia - pathology
Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group Proteins
Female
Germ Cells - pathology
Hematologic and hematopoietic diseases
Hematopoietic Cell Growth Factors - pharmacology
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - pathology
Infertility, Female - genetics
Interferon-gamma - pharmacology
Macrophage Inflammatory Proteins
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Monokines - pharmacology
Nuclear Proteins
Ovary - pathology
Proteins - genetics
Proteins - physiology
Recombinant Proteins - pharmacology
Single-Blind Method
Testis - pathology
Tumor Necrosis Factor-alpha - pharmacology
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Description
Summary:Fanconi anemia (FA) is an autosomal recessive chromosome instability syndrome characterized by progressive bone marrow (BM) failure, skeletal defects, and increased susceptibility to malignancy. FA cells are hypersensitive to DNA cross-linking agents, oxygen and have cell cycle abnormalities. To develop an animal model of the disease we generated mice homozygous for a targeted deletion of exon 9 of the murine FA complementation group C gene (fac). Mutant mice had normal neonatal viability and gross morphology, but their cells had the expected chromosome breakage and DNA cross-linker sensitivity. Surprisingly, male and female mutant mice had reduced numbers of germ cells and females had markedly impaired fertility. No anemia was detectable in the peripheral blood during the first year of life, but the colony forming capacity of marrow progenitor cells was abnormal in vitro in mutant mice. Progenitor cells from fac knock-out mice were hypersensitive to interferon gamma. This previously unrecognized phenotype may form the basis for BM failure in human FA.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V88.1.49.49