Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia

Abstract

Fanconi anaemia (FA) is an autosomal recessive disease characterized by bone marrow failure, variable congenital malformations and predisposition to malignancies. Cells derived from FA patients show elevated levels of chromosomal breakage and an increased sensitivity to bifunctional alkylating agents such as mitomycin C (MMC) and diepoxybutane (DEB). Five complementation groups have been identified by somatic cell methods, and we have cloned the gene defective in group C (FAC)(7). To understand the in vivo role of this gene, we have disrupted murine Fac and generated mice homozygous for the targeted allele. The -/- mice did not exhibit developmental abnormalities nor haematologic defects up to 9 months of age. However, their spleen cells had dramatically increased numbers of chromosomal aberrations in response to MMC and DEB. Homozygous male and female mice also had compromised gametogenesis, leading to markedly impaired fertility, a characteristic of FA patients. Thus, inactivation of Fac replicates some of the features of the human disease.

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

“…We and others have previously created strains of mice with targeted deletions of the murine Fanca, Fancc, and Fancg genes, all components of the FA nuclear complex. These mutants have very similar phenotypes (Chen et al 1996;Whitney et al 1996;Cheng et al 2000;Yang et al 2001;Koomen et al 2002;Noll et al 2002), supporting a model in which the components of the complex participate in a common function. To determine whether Fancd2 participates only in this function in vivo or has additional roles, we generated a strain of mice with a null allele in this gene.…”

“…Knockouts of Fancc (Chen et al 1996;Whitney et al 1996), Fanca (Cheng et al 2000;Noll et al 2002), and Fancg (Yang et al 2001;Koomen et al 2002) all share a defect in germ-cell development and demonstrate cellular sensitivity to agents that produce DNA interstrand cross-links (ICLs). In contrast to human FA patients, however, FA mice do not develop anemia and do not have skeletal defects; nor are they at an increased risk for developing cancer.…”

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

“…In other monozygotic twins with different phenotypes somatic mosacism was not detected. Additionally, in mouse models of Fanconi anaemia, in which somatic mosacism is not possible by virtue of both alleles carrying identical deletions, there is also a variable penetrance of the phenotype [18][19][20][21][22][23][24][25][26][27]. Hence, there is a stochastic element that contributes to the severity of the phenotype that is likely to be due to an endogenous or exogenous source of DNA damage.…”

“…In fact, all FA mouse models to date exhibit the same fertility defect [18][19][20][21][22][23][24][25][26][27]. FA mutant mice are born with extremely few germ cells in either the testis or the ovary.…”

Successful pregnancies after bone marrow transplantation for Fanconi anemia

“…3 Recent experimental studies showed that in animal models of FA, such as Fancg/Xrcc9 null mice or mice mutant for FA complementation group C, the number of germ cells was dramatically reduced, suggesting that FA complementation groups are required for mitotic proliferation of primordial germ cells. [4][5][6] However, the pathophysiology of ovarian failure has not been clearly elucidated in human females and no histo-pathologic study has been published. Causes may be multifactorial, as suggested by some FA patients presenting with hypergonadotropic hypogonadism caused by germ cell insufficiency, with or without associated pituitary stalk interruption.…”