Disease relevance of Fanca

• Mice with a targeted disruption of the Fanconi anemia homolog Fanca [1].
• Both male and female mice homozygous for Fanca mutation exhibit hypogonadism, and homozygous females demonstrate premature reproductive senescence and an increased incidence of ovarian cysts [2].
• Cells lacking Fanca exhibit increased chromosomal aberrations and attenuated accumulation of Brca1 and Rad51 foci in response to DNA damage [3].
• Mutations in Fanca account for the majority of cases of Fanconi anemia (FA), a recessively inherited disease identified by congenital defects, bone marrow failure, infertility, and cancer susceptibility [4].
• Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA [5].

High impact information on Fanca

• Fanca(tm1.1Hsc) homozygotes display FA-like phenotypes including growth retardation, microphthalmia and craniofacial malformations that are not found in other Fanca mouse models, and the genetic background affects manifestation of certain phenotypes [2].
• Fanca(tm1Hsc) homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination [2].
• To study the in vivo role of the FA group A gene (Fanca), gene-targeting techniques were used to generate Fanca(tm1Hsc) mice in which Fanca exons 1-6 were replaced by a beta-galactosidase reporter construct [2].
• We also found a high level of Fanca expression in pachytene spermatocytes [2].
• 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 [6].

Biological context of Fanca

• Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis [7].
• Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells [8].
• Zfp276 is expressed in the same tissues as Fanca, but does not complement the mitomycin C (MMC)-sensitive phenotype of FA-A cells [9].
• Fanca is located at the distal region of mouse chromosome 8 and has a ubiquitous pattern of expression in embryonic and adult tissues [9].
• Upon transfection into Fanca-deficient mouse embryonic fibroblasts EGFP-Fancg chimeric protein was detectable in the nucleus [10].

Anatomical context of Fanca

• In addition, Fanca gene expression was confined to mature pituitary gonadotrophs and adult mouse pituitary and was not expressed in the immature alpha T3-1 gonadotroph cell line [4].
• Based on Northern as well as Western blots, Fanca was mainly expressed in lymphoid tissues, testis, and ovary [11].
• At the cellular level, no difference in the radiosensitivity of normal and FA-A lymphoblast cells was noted, and a modest increase in the radiosensitivity of Fanca-/- hematopoietic progenitor cells was observed compared to Fanca+/+ cells [12].

Other interactions of Fanca

• We show that the targeted deletion of Fanca exons 37-39 generates a null for Fanca in mice and abolishes ubiquitination of Fancd2, the downstream effector of the FA complex [3].

Analytical, diagnostic and therapeutic context of Fanca

• By in situ hybridization, Fanca transcripts were found in the whisker follicles, teeth, brain, retina, kidney, liver, and limbs [7].
• In addition, mouse Fancg and Fanca proteins co-purify by immunoprecipitation [10].
• We confirmed expression and hormonal regulation of Fanca mRNA by quantitative RT-PCR, which showed that GnRH induced a rapid, transient increase in Fanca mRNA [4].
• Finally, when animals were exposed to a fractionated total-body irradiation of 5 Gy, a similar hematopoietic syndrome was observed in wild-type and Fanca-/- mice [12].

References