Targeted disruption of the murine Fanconi anemia gene, Fancg/Xrcc9

Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility di sorder characterized by cellular sensitivity to mitomycin C and ionizing ra diation. Six FA genes (corresponding to subtypes A, C, D2, E, F, and G) hav e been cloned, and the encoded FA proteins interact in a common cellular pa thway. 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 ho mozygous for the targeted allele. Similar to the phenotype of the previousl y described Fancc(-/-) and Fanca(-/-) mice, the Fancg(-/-) mice had normal viability and no gross developmental abnormalities. Primary splenic lymphoc ytes, 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. Fan cg(-/-) lymphocytes had a defect in the FA pathway, based on their failure to activate the monoubliquitination of the downstream Fancd2 protein in res ponse 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. (Bl ood. 2001;98:3435-3440) (C) 2001 by The American Society of Hematology.