title: Targeted disruption of the murine Fanconi anemia gene, Fancg/Xrcc9.
abstract: Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Six FA genes (corresponding to subtypes A, C, D2, E, F, and G) have been cloned, and the encoded FA proteins interact in a common cellular pathway. To further understand the in vivo role of one of these human genes (FANCG), we generated a targeted disruption of murine Fancg and bred mice homozygous for the targeted allele. Similar to the phenotype of the previously described Fancc(-/-) and Fanca(-/-) mice, the Fancg(-/-) mice had normal viability and no gross developmental abnormalities. Primary splenic lymphocytes, bone marrow progenitor cells, and murine embryo fibroblasts from the Fancg(-/-) mice demonstrated spontaneous chromosome breakage and increased sensitivity to mitomycin C and, to a lesser extent, ionizing radiation. Fancg(-/-) lymphocytes had a defect in the FA pathway, based on their failure to activate the monoubiquitination of the downstream Fancd2 protein in response to IR. Finally, Fancg(-/-) mice had decreased fertility and abnormal gonadal histology. In conclusion, disruption of the Fancg gene confirms the role of Fancg in the FA pathway. The Fancg(-/-) mouse may be useful as an animal model for future gene therapy and cancer susceptibility studies.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Kuang
authors.forename: R
authors.initials: R
authors.lastname: Montes De Oca
authors.forename: T
authors.initials: T
authors.lastname: Hays
authors.forename: L
authors.initials: L
authors.lastname: Moreau
authors.forename: N
authors.initials: N
authors.lastname: Lu
authors.forename: B
authors.initials: B
authors.lastname: Seed
authors.forename: A D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000483:Alleles; D000818:Animals; D019457:Chromosome Breakage; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000235:genetics*; D052241:Fanconi Anemia Complementation Group G Protein; D006412:Hematopoietic Stem Cells / Q000648:ultrastructure; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007246:Infertility / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D016296:Mutagenesis; D010641:Phenotype; D013154:Spleen / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; C499909:FANCG protein, human; C499910:Fancg protein, mouse; D052241:Fanconi Anemia Complementation Group G Protein; D016685:Mitomycin