Developmental Expression of the Fac Gene Correlates with Congenital Defects in Fanconi Anemia Patients

Abstract

Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by a variety of congenital and skeletal malformations, progressive pancytopaenia and predisposition to malignancies. While the basic defect in this disease is not known, the cloning of the gene defective in FA group C patients (FAC) allows analysis of its expression pattern, which may provide clues about the functional properties of the protein. This paper describes the distribution of Fac transcripts during murine development (8-19.5 days p.c.), using RNA in situ hybridization. Fac is initially expressed (8-10 days p.c.) in the mesenchyme and its derivatives with osteogenic potential. The transcript is also apparent at later stages of bone development (13-19.5 days p.c.), localized to cells of the inner perichondrium, periosteum and zone of endochondral ossification. In the latter, Fac transcripts are seen in cells from both osteogenic and hematopoietic lineages. Fac mRNA is also seen in intramembranous cranial and facial bones. In addition, Fac signal is detected in non-skeletal tissues: brain, whisker follicles, lung, kidney, gut and stomach. Fac expression is high in progenitor cell populations but is downregulated in differentiating cells that give rise to connective tissue. The pattern of Fac expression is consistent with the skeletal and non-skeletal congenital abnormalities in FA patients. As well, expression in rapidly dividing progenitors is consistent with hypotheses regarding the nature of the basic defect in FA: a role of the protein in DNA repair or protection from oxygen toxicity.

Molecular Genetics and Fanconi Anaemia: New Insights Into Old Problems

“…Thus sensitivity to apoptosis could potentially explain both the haemopoietic defects in FA, due to stem cell apoptosis, and many of the developmental defects in FA, due to exaggerated cell death during organ and limb morphogenesis ( Garcia‐Martinez et al , 1993 ). In fact the pattern of FAC transcripts observed by in situ hybridization to normal murine embryos was consistent with the skeletal and non‐skeletal congenital abnormalities seen in FA patients ( Krasnoshtein & Buchwald, 1996). Moreover, forced overexpression of the FAC gene was shown to inhibit apoptosis in cytokine‐dependent cell lines ( Cumming et al , 1996 ).…”

Fanconi anemia genes are highly expressed in primitive CD34+hematopoietic cells

“…Murine Brca1 and Brca2 mRNA expression was shown to be up-regulated in rapidly proliferating cells indicative of a role in proliferation and differentiation control [37]. Also, murine Fancg mRNA was shown to be expressed in highly proliferative and embryonic tissues [31]. Since Fancc -/- progenitor/stem cells were shown to be less quiescent [36], our results showing increased Brca1 and Brca2/Fancd1 mRNA expression levels in Fancc -/- BM cells would be consistent with an altered proliferation state.…”

Mouse models of Fanconi anemia

“…Like the FancA -/- mice, the relatively mild phenotype of FancC -/- mice is remarkable in view of the fact that: 1) the cellular defect in FancA -/- and FancC -/- MEFs is similar to that of FA cells (11); 2) the mouse genes correct human FA cells of the same complementation group, demonstrating conservation of function between mice and humans (79, 81, 84); 3) FancA and FancC are highly expressed in mouse embryos in tissues prone to developmental defects in FA (1, 38); 4) FancC -/- mice are hypersensitive to crosslinking agents (8) and chronic in vivo exposure to a low dose of MMC induces chromosomal aberrations and progressive bone marrow failure with pancytopenia (26, 58, 62, 82). Clearly mice defective in the FA pathway, like humans, are hypersensitive to DNA interstrand crosslinks, leading to the possibility that the mild phenotype in mice could be due to fewer spontaneous DNA lesions.…”