Mice with a targeted disruption of the Fanconi anemia homolog Fanca

Abstract

Fanconi anemia (FA) is a hereditary chromosomal instability syndrome with cancer predisposition. Bone marrow failure resulting in pancytopenia is the main cause of death of FA patients. Diagnosis of FA is based on their cellular hypersensitivity to DNA crosslinking agents and chromosome breakages. Somatic complementation experiments suggest the involvement of at least eight genes in FA. The gene for complementation group A (FANCA) is defective in the majority of FA patients. We show here that mice deficient of FANCA: are viable and have no detectable developmental abnormalities. The hematological parameters showed a slightly decreased platelet count and a slightly increased erythrocyte mean cell volume in mice at young age, but this did not progress to anemia. Consistent with the clinical phenotype of FA patients, both male and female mice showed hypogonadism and impaired fertility. Furthermore, embryonic fibroblasts of the knock-out mice exhibited spontaneous chromosomal instability and were hyper-responsive to the clastogenic effect of the crosslinker mitomycin C.

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.…”

“…Plates were frozen at −80°C. Total DNA was quantified using CyQuant (Molecular Probes) and compared with untreated controls as an indication of cell growth as previously described (Cheng et al 2000). Quantification of DNA using CyQuant was performed using a Fluorstar plate reader (B&L Systems) according to the manufacturer's instructions.…”

“…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.…”

Fanconi Anemia — Case Report of Rare Aplastic Anemia at Child

“…Bone marrow transplantation is the only treatment that defi nitively restores hematopoiesis at patients. In 2000 the median age at death reached 30, probably because of better medical care, compared to 1980 when median age at death was 20 and even less [4,9,11].…”

“…Clinically, the aff ected FA patient may present with bleeding, pallor and recurrent infections. Certain cytogenetic abnormalities are commonly seen in FA patients including monosomy 5 and monosomy 7 [4]. Chromosomal instability, especially on exposure to alkylating agents (mitomycin C or diepoxybutane) are useful for a diagnostic test [5].…”