title: Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene.
abstract: 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.
authors.affiliation: Department of Molecular and Medical Genetics, Vollum Institute, Oregon Regional Primate Center, Portland, USA
authors.forename: M A
authors.initials: MA
authors.lastname: Whitney
authors.forename: G
authors.initials: G
authors.lastname: Royle
authors.forename: M J
authors.initials: MJ
authors.lastname: Low
authors.forename: M A
authors.initials: MA
authors.lastname: Kelly
authors.forename: M K
authors.initials: MK
authors.lastname: Axthelm
authors.forename: C
authors.initials: C
authors.lastname: Reifsteck
authors.forename: S
authors.initials: S
authors.lastname: Olson
authors.forename: R E
authors.initials: RE
authors.lastname: Braun
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: R K
authors.initials: RK
authors.lastname: Rathbun
authors.forename: G C
authors.initials: GC
authors.lastname: Bagby
authors.forename: M
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D054407:Chemokine CCL4; D002869:Chromosome Aberrations; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005854:Germ Cells / Q000473:pathology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D007247:Infertility, Female / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D019402:Macrophage Inflammatory Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D015846:Monokines / Q000494:pharmacology; D009687:Nuclear Proteins; D010053:Ovary / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D016037:Single-Blind Method; D013737:Testis / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D054407:Chemokine CCL4; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D016298:Hematopoietic Cell Growth Factors; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma