Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice.
Fanconi anemia (FA) is a heterogeneous autosomal recessive chromosomal instability syndrome associated with diverse developmental abnormalities, progressive bone marrow failure and a predisposition to cancer. Spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents characterize the cellular FA phenotype. The gene affected in FA complementation group G patients was initially identified as XRCC9, for its ability to partially correct the cellular phenotype of the Chinese hamster ovary (CHO) cell mutant UV40. By targeted disruption we generated Fancg/Xrcc9 null mice. Fancg knock-out (KO) mice were born at expected Mendelian frequencies and showed normal viability. In mice, functional loss of Fancg did not result in developmental abnormalities or a pronounced incidence of malignancies. During a 1 year follow-up, blood cell parameters of Fancg KO mice remained within normal values, revealing no signs of anemia. Male and female mice deficient in Fancg showed hypogonadism and impaired fertility, consistent with the phenotype of FA patients. Mouse embryonic fibroblasts (MEFs) from the KO animals exhibited the FA characteristic cellular response in showing enhanced spontaneous chromosomal instability and a hyper-responsiveness to the clastogenic and antiproliferative effects of the cross-linking agent mitomycin C (MMC). The sensitivity to UV, X-rays and methyl methanesulfonate, reported for the CHO mutant cell line UV40, was not observed in Fancg(-/-) MEFs. Despite a lack of hematopoietic failure in the KO mice, clonogenic survival of bone marrow cells in vitro was strongly reduced in the presence of MMC. The characteristics of the Fancg(-/-) mice closely resemble those reported for Fancc and Fanca null mice, supporting a tight interdependence of the corresponding gene products in a common pathway.
Koomen
Mireille
M
Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Cheng
Ngan C
NC
van de Vrugt
Henri J
HJ
Godthelp
Barbara C
BC
van der Valk
Martin A
MA
Oostra
Anneke B
AB
Zdzienicka
Malgorzata Z
MZ
Joenje
Hans
H
Arwert
Fré
F
D000818:Animals; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004342:Drug Hypersensitivity; D005199:Fanconi Anemia / Q000235:genetics; D052241:Fanconi Anemia Complementation Group G Protein; D005260:Female; D005347:Fibroblasts; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology*; D010053:Ovary / Q000002:abnormalities; D013737:Testis / Q000002:abnormalities
D004268:DNA-Binding Proteins; C499910:Fancg protein, mouse; D052241:Fanconi Anemia Complementation Group G Protein; D016685:Mitomycin; D004247:DNA